Formulations Of Apremilast

ABSTRACT

Provided herein are oral dosage forms comprising a) a core tablet comprising (i) a drug layer comprising apremilast and hypromellose acetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) a swellable layer comprising one or more swellable polymers; and b) a coating layer disposed on the core tablet, wherein the oral dosage form surface comprises at least one drug release orifice. The disclosed oral dosage forms provide once-a-day dosing of apremilast and are suitable for treating diseases or disorders ameliorated by inhibiting phosphodiesterase subtype IV (PDE4).

BACKGROUND

Apremilast is a phosphodiesterase subtype IV (“PDE4”) inhibitor and hasbeen approved worldwide for the treatment of various diseases associatedwith inflammation. For example, in the United States apremilast isapproved for the treatment of adult patients with moderate to severeplaque psoriasis who are candidates for phototherapy or system therapy,for the treatment of adult patients with active psoriatic arthritis, andfor the treatment of adult patients with oral ulcers associated withBehcet's Disease. Apremilast was the first, and remains the only, orallyadministered PDE4 inhibitor approved for the treatment of theseinflammatory diseases. The recommended dosage for adult patients withactive PsA and psoriasis is 30 mg twice daily (BID) orally, following a5-day titration that is intended to reduce the gastrointestinal (GI)symptoms associated with initial therapy.

A goal in developing a drug is to provide dosage forms which make itpossible to maintain a certain amount or concentration of drug in asubject's body that is clinically or therapeutically relevant. In somecases, this may not be achieved by traditional rapidly disintegratingtablets, as these tablets release the active ingredient containedtherein all at once.

In view of the foregoing, there remains a need for oral dosage forms ofapremilast that provide clinically desirable drug exposure.

SUMMARY

The disclosure provides oral dosage forms comprising a core tabletcomprising (i) a drug layer comprising apremilast and hypromelloseacetate succinate (HPMCAS) in an amorphous solid dispersion; and (ii) aswellable layer comprising one or more swellable polymers; and a coatinglayer disposed on the core tablet, wherein the oral dosage form surfacecomprises at least one drug release orifice.

The disclosure further provides oral dosage forms comprising a coretablet comprising (i) a drug layer comprising 8-11 wt % apremilast basedupon total core tablet weight, 8-11 wt % hypromellose acetate succinate(HPMCAS) based upon total core tablet weight, 2-7 wt % mannitol basedupon total core tablet weight, 40-45 wt % polyethylene oxide based upontotal core tablet weight, 0.1-0.5 wt % magnesium stearate based upontotal core tablet weight, and 0.1-0.5 wt % colloidal silicon dioxidebased upon total core tablet weight, wherein the apremilast and HPMCASare in a solid dispersion; (ii) a swellable layer comprising 18-25 wt %polyethylene oxide based upon total core tablet weight, 7-10 wt %microcrystalline cellulose based upon total core tablet weight, 1.5-3.5wt. % sodium chloride based upon total core tablet weight, 0.01-0.2 wt %iron oxide based upon total core tablet weight, and 0.05-0.3 wt %magnesium stearate based upon total core tablet weight; and a coatinglayer disposed on the core tablet and comprising cellulose acetate andpolyethylene glycol; wherein the oral dosage form surface comprising atleast one drug release orifice.

The disclosure also provides oral dosage forms comprising a core tabletcomprising (i) a drug layer comprising 10-15 wt. % apremilast based upontotal core tablet weight, 10-15 wt % hypromellose acetate succinate(HPMCAS) based upon total core tablet weight, 30-40 wt % polyethyleneoxide based upon total core tablet weight, 2-8 wt % sodium chloridebased upon total core tablet weight, 0.1-0.5 wt % magnesium stearatebased upon total core tablet weight, and 0.1-0.5 wt % colloidal silicondioxide based upon total core tablet weight, wherein the apremilast andHPMCAS are in a solid dispersion; (ii) a swellable layer comprising18-25 wt % polyethylene oxide based upon total core tablet weight,7.5-10.0 wt % microcrystalline cellulose based upon total core tabletweight, 2-4 wt % sodium chloride based upon total core tablet weight,0.01-0.1 wt % iron oxide based upon total core tablet weight, and0.05-0.3 wt % magnesium stearate based upon total core tablet weight;and a coating layer disposed on the core tablet and comprising celluloseacetate and polyethylene glycol; wherein the oral dosage form surfacecomprising at least one drug release orifice.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows dissolution profiles of Tablets 6-10.

FIG. 2 shows dissolution profiles of Tablets 1-5.

FIG. 3 shows dissolution profiles of tablet core 5 uncoated or with a CAor PEG coating.

FIG. 4 shows dissolution profiles of Tablets 10-12.

FIG. 5 shows Mean (±SD) Apremilast Plasma Concentrations—Time Profiles.

FIG. 6 shows apremilast plasma concentrations over 24 hours of 75 mgTablet 21 once a day (open circles), compared to a 30 mg immediaterelease formulation twice a day (filled circles) and 75 mg gastrorentive(GR) tablet once a day (filled diamonds).

FIG. 7 shows apremilast plasma concentrations over 5 days of 75 mgTablet 21 once a day (open circles), compared to a 30 mg immediaterelease formulation twice a day (filled circles) and 75 mg gastrorentive(GR) tablet once a day (filled diamonds).

FIG. 8 shows the dissolution of Core Tablet Compositions 7-1 through7-6.

FIG. 9 shows the dissolution of Core Tablet Compositions 7-7 through7-12.

FIG. 10A shows decreased dissolution of Core Tablet Composition 7-8after various storage conditions.

FIG. 10B shows increased crystallinity in Core Tablet Composition 7-8after various storage conditions.

FIG. 11A shows dissolution of Core Tablet Compositions 7-12 aftervarious storage conditions.

FIG. 11B shows comparison of crystallinity in Core Tablet Composition7-8 and 7-12 after various storage conditions.

DETAILED DESCRIPTION

Provided herein are oral dosage forms suitable for providing once-a-day(QD) dosing of apremilast. In some embodiments, the disclosed oraldosage forms are administered under fed conditions.

The oral dosage forms disclosed herein comprise a core tablet, a coatinglayer disposed on the core tablet, and at least one drug releaseorifice. In some embodiments, the oral dosage forms further comprise asub-coat layer between the core tablet and the coating layer.

Core Tablet

The core tablet of the disclosed oral dosage forms comprises i) a druglayer comprising apremilast and hypromellose acetate succinate (HPMCAS)in an amorphous solid dispersion and ii) a swellable layer comprisingone or more swellable polymers.

Drug Layer

The drug layer comprises a suitable amount of apremilast. Desirably, thedrug layer contains an amount of apremilast that is suitable to provideonce-a-day delivery/dosing of apremilast. If the oral dosage formscomprise too little apremilast, then the dosage forms will not deliver aclinically suitable amount of apremilast and will not be efficaciouswhen dosed QD. Conversely, if the oral dosage forms comprise too muchapremilast then the dosage forms are inefficient in their use ofapremilast and overly costly. Moreover, if too much or too littleapremilast is present then the bioequivalence of the dosage forms and/orthe flux and release of apremilast from the dosage forms can benegatively impacted. In some embodiments, the apremilast is present inan amount of 6-15 wt % of the core tablet. Some examples of contemplatedamounts of apremilast include, but are not limited to, 6.0, 6.1, 6.2,6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6,7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0,9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9, 10.0, 10.1, 10.2, 10.3,10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1, 11.2, 11.3, 11.4, 11.5,11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3, 12.4, 12.5, 12.6, 12.7,12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5, 13.6, 13.7, 13.8, 13.9,14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7, 14.8, 14.9, 15.0, 15.1,15.2, 15.3, 15.4, 15.5, 15.6, 15.7, 15.8, 15.9, and 16.0 wt % of thecore tablet. In some embodiments, the apremilast is present in an amountof 8-11 wt % of the core tablet. In various embodiments, the apremilastis present in an amount of 9.6 wt % of the core tablet, 10.2 wt % of thecore tablet, or 12.5 wt % of the core tablet.

In some embodiments, in conjunction with other above or belowembodiments, the oral dosage forms comprise a total amount of 25-100 mgapremilast (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or 100 mg apremilast). In someembodiments, in conjunction with other above or below embodiments, theoral dosage forms comprise 25-30 mg apremilast or 50-100 mg apremilast(e.g., 50-60 mg or 65-85 mg apremilast). In various embodiments, inconjunction with other above or below embodiments, the oral dosage formscomprise 70, 75, or 80 mg apremilast. In some embodiments, the oraldosage forms comprises 27.5 mg apremilast, 55 mg of apremilast, 75 mgapremilast, or 100 mg apremilast.

In addition to apremilast, the drug layer also comprises HPMCAS. As usedherein, HPMCAS refers to a family of cellulose derivatives that can have(1) two types of ether substituents, methyl and/or 2-hydroxypropyl and(2) two types of ester substituents, acetyl and/or succinyl. HPMCAS isalso known by the chemical name O-(2-hydroxypropyl)-O-methyl-celluloseacetate succinate. The degree of substitution for each of the fourgeneral types just noted can be varied over a wide range to affect thechemical and physical properties of the polymer. This versatility ofHPMCAS allows its structure to be optimized to obtain good performancewith a particular drug of interest. HPMCAS can be synthesized orpurchased commercially. Three examples of commercially available HPMCASinclude Shin-Etsu AQOAT®-LF, Shin-Etsu AQOAT®-MF, and Shin-EtsuAQOAT®-HF. All three of these polymers are manufactured by Shin-EtsuChemical Co., Ltd. (Tokyo, Japan). In some embodiments, the HPMCAS is Lgrade (e.g., HPMCAS-LF or HPMCAS-LG or HPMCAS-LMP), wherein it isunderstood that L, M, and H grades of HPMCAS vary in acetyl andsuccinoyl contents. The L, M and H grades also refer to the pH at whichthe polymers dissolve (L=low pH≥5.5, M=medium pH≥6.0 and H=high pH≥6.5).LF, LG and LMP grades refer to differing average particle size (F iscohesive fine powder—5 μm, MP is medium particle size—200 μm and G isfree-flowing granules—1000 μm).

The HPMCAS has any suitable molecular weight. In some embodiments, themean weight-average molecular weight range for HPMCAS is 10,000 to onemillion daltons (e.g., 10,000 to 400,000 daltons or 55,000 to 115,000daltons, as determined using polyethylene oxide standards). Note thatmolecular weight can be presented herein as daltons (Da) or as g/mol,which are used interchangeably throughout. The molecular weight rangecan also vary based on the degree of substitution (e.g., amount ofacetyl and/or succinyl groups present). For example, in variousembodiments, in conjunction with other above or below embodiments, themean weight-average molecular weight of the HPMCAS is approximately15,000 to 20,000 daltons, for example, 15,000, 16,000, 17,000, 18,000,19,000, or 20,000 daltons. In some embodiments, mean weight-averagemolecular weight of the HPMCAS is 17,700, 17,900, 18,800, 18,900,20,400, or 21,200 daltons. In some embodiments, in conjunction withother above or below embodiments, the number-average molecular weight isapproximately 13,000 daltons.

The drug layer comprises a suitable amount of HPMCAS. If the drug layercomprises too little or too much HPMCAS, then the amorphous soliddispersion may not have the desired release properties. In someembodiments, the HPMCAS is present in an amount of 6-15 wt % of the coretablet (e.g. 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, 8.0, 8.1, 8.2, 8.3, 8.4, 8.5,8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3, 9.4, 9.5, 9.6, 9.7, 9.8, 9.9,10.0, 10.1, 10.2, 10.3, 10.4, 10.5, 10.6, 10.7, 10.8, 10.9, 11.0, 11.1,11.2, 11.3, 11.4, 11.5, 11.6, 11.7, 11.8, 11.9, 12.0, 12.1, 12.2, 12.3,12.4, 12.5, 12.6, 12.7, 12.8, 12.9, 13.0, 13.1, 13.2, 13.3, 13.4, 13.5,13.6, 13.7, 13.8, 13.9, 14.0, 14.1, 14.2, 14.3, 14.4, 14.5, 14.6, 14.7,14.8, 14.9, or 15.0 wt % of the core tablet). In some embodiments, theHPMCAS is present in an amount of 8-11 wt % of the core tablet. Invarious embodiments, the HPMCAS is present in an amount of 9.6 wt. % ofthe core tablet, 10.2 wt % of the core tablet, or 12.5 wt % of the coretablet.

In some embodiments, in conjunction with other above or belowembodiments, the oral dosage forms comprise a total amount of 25-100 mgHPMCAS (e.g., 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 94, 95, 96, 97, 98, 99, or 100 mg HPMCAS). In some embodiments, inconjunction with other above or below embodiments, the oral dosage formscomprise 65-85 mg of HPMCAS. In various embodiments, in conjunction withother above or below embodiments, the oral dosage forms comprise 25-30mg HPMCAS or 50-100 mg HPMCAS (e.g., 50-60 mg or 65-85 mg HPMCAS). Invarious embodiments, in conjunction with other above or belowembodiments, the oral dosage forms comprise 70, 75, or 80 mg HPMCAS. Insome embodiments, the oral dosage forms comprises 27.5 mg HPMCAS, 55 mgof HPMCAS, 75 mg HPMCAS, or 100 mg HPMCAS.

In various embodiments, the apremilast and HPMCAS are present in aweight ratio of 40:60 to 60:40 in the core tablet. For example, in someembodiments, the apremilast:HPMCAS weight ratio in the core tablet is:40:60, 41:59, 42:58, 43:57, 44:56, 45:55, 46:56, 47:53, 48:52, 49:51,50:50, 51:49, 52:48, 53:47, 54:46, 55:45, 56:44, 57:43, 58:42, 59:41, or60:40. In some embodiments, the apremilast and HPMCAS are present in aweight ratio of 45:55 to 55:45 in the core tablet. In variousembodiments, the apremilast and HPMCAS are present in a weight ratio of48:52 to 52:48 in the core tablet. In some embodiments, the apremilastand HPMCAS are present in a weight ratio of 50:50 in the core tablet.

Amorphous Solid Dispersion

The apremilast and HPMCAS are present as an amorphous solid dispersionin the core tablet. Without wishing to be bound to any particulartheory, it is believed that that the amorphous solid dispersion providesimproved bioavailabilty of apremilast due to, for example, 1) improveddrug dispersion, thereby preventing or retarding the rate ofcrystallization in the solid state, 2) improved dissolution in vivo,thereby allowing the drug to be released in the gastrointestinal tract,and 3) inhibiting the precipitation or crystallization of aqueousdissolved drug. Apremilast is required to be maintained amorphous in thecomposition disclosed herein, as it has been found that small amounts(e.g., 1.5 wt % or less) of crystalline apremilast can result in slowerdissolution of the solid dispersion.

In some embodiments, in conjunction with other above or belowembodiments, the amorphous solid dispersion is spray-dried. It has beenfound that a spray-dried solid dispersion (SDD) of apremilast in HPMCASprovide unexpectedly good solubility and improved ease of formulation.As is understood, spray-drying refers to processes involving breaking upliquid mixtures into small droplets (atomization) and rapidly removingsolvent from the mixture in a container where there is a strong drivingforce for evaporation of solvent from the droplets. The strong drivingforce for solvent evaporation is generally provided by maintaining thepartial pressure of solvent in the spray-drying apparatus well below thevapor pressure of the solvent at the temperature of the drying droplets.This is accomplished by (1) maintaining the pressure in the spray-dryingapparatus at a partial vacuum (e.g., 0.01-0.50 atm); (2) mixing theliquid droplets with a warm drying gas; or (3) both. For example, asolution of a drug and HPMCAS in acetone can be suitably spray-dried byspraying the solution at a temperature of 50° C. (the vapor pressure ofacetone at 50° C. is about 0.8 atm) into a chamber held at 0.01-0.2 atmtotal pressure by connecting the outlet to a vacuum pump. Alternatively,the acetone solution can be sprayed into a chamber where it is mixedwith nitrogen or other inert gas at a temperature of 80-180° C. and apressure of 1.0-1.2 atm.

Generally, the temperature and flow rate of the drying gas is chosen sothat the HPMCAS/drug-solution droplets are dry enough by the time theyreach the wall of the apparatus that they are essentially solid, so thatthey form a fine powder and do not stick to the apparatus wall. Theactual length of time to achieve this level of dryness depends on thesize of the droplets. Droplet sizes generally range from 1 μm to 500 μmin diameter, with 5 to 100 μm being more typical. The largesurface-to-volume ratio of the droplets and the large driving force forevaporation of solvent leads to actual drying times of a few seconds orless. This rapid drying is important to the particles maintaining auniform, homogeneous composition instead of separating into drug-richand polymer-rich phases. Such dispersions which have a homogeneouscomposition can be considered solid solutions and may be supersaturatedin drug. Such homogeneous dispersions are preferred in that the maximumsupersaturated concentration (MSSC) value obtained when a large amountof drug is dosed can be higher for such dispersions relative todispersions for which at least a portion of the drug is present as adrug-rich amorphous or crystalline phase. Solidification times should beless than 20 seconds, preferably less than 5 seconds, and morepreferably less than 2 seconds. In general, to achieve this rapidsolidification of the drug/polymer solution, it is preferred that thesize of droplets formed during the spray drying process are less than100 μm in diameter, preferably less than 50 μm in diameter, and morepreferably less than 25 μm in diameter. The resultant solid particlesthus formed are generally less than 100 μm in diameter, preferably lessthan 50 μm in diameter, more preferably less than 25 μm in diameter.

Following solidification, the solid powder may stay in the spray-dryingchamber for 5-50 seconds, further evaporating solvent from the solidpowder. The final solvent content of the solid dispersion as it exitsthe dryer should be low, since this reduces the mobility of drugmolecules in the dispersion, thereby improving its stability. Generally,the residual solvent content of the dispersion should be less than 10 wt% and preferably less than 2 wt %.

The dispersions can then be post-processed to prepare them foradministration using methods known in the art such as roller compaction,fluid bed agglomeration, or spray coating. Spray-drying processes andspray-drying equipment are described generally in, for example, ChemicalEngineers' Handbook, Sixth Edition (R. H. Perry, D. W. Green, J. O.Maloney, eds.) McGraw-Hill Book Co. 1984, page 20-54 to 20-57. Moredetails on spray-drying processes and equipment are reviewed by Marshall(“Atomization and Spray-Drying,” Chem. Eng. Prog. Monogr. Series, 50[1954] 2).

In some embodiments, the solution spray-dried to form theHPMCAS/apremilast dispersion contains only apremilast and HPMCAS in asolvent. In some embodiments, the ratio of apremilast to HPMCAS in thesolution is 0.2-1.2 to 1-100 or 0.4-1.2 to 1-20. In some embodiments,the ratio of apremilast to HPMCAS in the spray-drying solution is1.2-0.8 to 1. Solvents suitable for spray-drying can be any organiccompound in which the apremilast and HPMCAS are mutually soluble.Preferably, the solvent is also volatile with a boiling point of 150° C.or less. In some embodiments, the solvents include alcohols such asmethanol, ethanol, n-propanol, iso-propanol, and butanol; ketones suchas acetone, methyl ethyl ketone and methyl iso-butyl ketone; esters suchas ethyl acetate and propyl acetate; and various other solvents such asacetonitrile, methylene chloride, toluene, and 1,1,1-trichloroethane.Lower volatility solvents such as dimethyl acetamide ordimethylsulfoxide can also be used. Mixtures of solvents can also beused, as can mixtures with water as long as the polymer and HPMCAS aresufficiently soluble to make the spray-drying process practical. In someembodiments, the solvent comprises acetone.

In some embodiments, spray-dried solutions and the resulting dispersionscan also contain various excipients/additives that aid in the stability,dissolution, tableting, or processing of the dispersion, as describedherein. In some embodiments, examples of such additives include:surfactants, pH-controlling substances (e.g., acids, bases, buffers),diluents/fillers, disintegrants, lubricants, or binders. Suchexcipients/additives, when present, can be added directly to thespray-drying solution such that the additive is dissolved or suspendedin the solution as a slurry. Alternatively, such additives can be addedfollowing the spray-drying process to aid in forming the final dosageform.

Water Soluble Polymer

In some embodiments, the drug layer comprises a water soluble polymer.The water soluble polymer in the drug layer, when present, is anysuitable water soluble polymer. Suitable water soluble polymers include,for example, polyethylene oxide, and a combination thereof. In variousembodiments, the water soluble polymer is polyethylene oxide.

The water soluble polymer in the drug layer has a suitable molecularweight. For example, in embodiments wherein the water soluble polymer inthe drug layer is polyethylene oxide (PEO), the polyethylene oxide hasan average molecular weight of 200,000 Da or higher. In someembodiments, the polyethylene oxide has an average molecular weight of200,000 Da to 300,000 Da (e.g., 200,000 and/or 300,000 Da), and/or600,000 Da. It has been discovered that some embodiments exhibitimproved stability wherein the drug layer comprises polyethylene oxidehaving more than one average molecular weight (e.g., a mixture ofpolyethylene oxides). For example, in embodiments wherein the drug layercomprises a mixture of polyethylene oxides of molecular weight of200,000 Da and 300,000 Da, the amount of crystalline apremilast thatforms during some stability studies (e.g., accelerated stabilitystudies) is less than in embodiments comprising only one low molecularweight polyethylene oxide (e.g., molecular weight of 200,000 Da). Insome cases, the polyethylene oxide is a mixture of 1 to 1 by weight 200kDa PEO to 300 kDa PEO. In some cases, the polyethylene oxide is amixture of 20:80 by weight 200 kDa PEO to 300 kDa PEO. In some cases,the polyethylene oxide is 300 kDa PEO. Certain embodiments comprisinghigh molecular weight polyethylene oxides (e.g., molecular weight of atleast 300,000 Da), and further comprising an osmotic agent (e.g., sodiumchloride) in the drug layer, may provide improved dissolution, lag times(e.g., reduced lag time), and stability.

Illustrative polyethylene oxides suitable for the drug layer is thePOLYOX WSR line of PEO commercially available from Dupont (Midland,Mich.), including POLYOX® WSR N80, POLYOX® WSR N750, and POLYOX® WSR205. POLYOX® WSR N80 (commercially available from Dupont; Midland,Mich.) has the following physical properties: MW of 200,000 Da;viscosity of 65-115 cP; silicon dioxide content of 0.8-3.0 wt %;particle size through 10 mesh: 100 min; particle size through 20 mesh:96-100 min; POLYOX® WSR N750 (commercially available from Dupont;Midland, Mich.) has the following physical properties: MW of 300,000 Da;viscosity of 600-1,200 cP; silicon dioxide content of 0.8-3.0 wt %;particle size through 10 mesh: 100 min; particle size through 20 mesh:96-100 min; and POLYOX® WSR 205 (commercially available from Dupont;Midland, Mich.) has the following physical properties: MW of 600,000 Da;viscosity of 6800-8800 cP; and silicon dioxide content of 0.8-3.0 wt %.

The water soluble polymer is present in a suitable amount. For example,in some embodiments, the water soluble polymer is present in an amountof 30-55 wt % of the core tablet (e.g., 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, or55 wt % of the core tablet). In some embodiments, the water solublepolymer is present in an amount of 30-55, 35-50, 35-45, 35-40, 40-55,40-50, 45-55, or 45-50 wt % of the core tablet. In some embodiments, inconjunction with other above or below embodiments, the water solublepolymer (e.g., polyethylene oxide) is present in 34.3 wt % of the coretablet, 35 wt % of the core tablet, 37.6 wt % of the core tablet, or42.7 wt % of the core tablet. In various embodiments, in conjunctionwith other above or below embodiments, the water soluble polymer andapremilast are present in a weight ratio of 2-6 to 1 in the drug layer.For example, in various embodiments the weight ratio of water solublepolymer to apremilast in the drug layer is 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9,4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3,5.4, 5.5, 5.6, 5.7, 5.8, 5.9, or 6.0 to 1. In some embodiments, inconjunction with other above or below embodiments, the weight ratio ofwater soluble polymer to apremilast in the drug layer is 2.7, 2.8, 3.0,3.7, 4.2, or 5.1 to 1.

In some embodiments, the oral dosage forms comprise 100 mg or morepolyethylene oxide in the drug layer, for example, 105, 110, 115, 120,or 125 mg polyethylene oxide in the drug layer. In some embodiments, theoral dosage forms comprise 200 mg or more polyethylene oxide in the druglayer, for example, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250,255, 260, 265, 270, 275, 280, 285, or 290 mg polyethylene oxide in thedrug layer. In some embodiments, the oral dosage forms comprise 300 mgor more polyethylene oxide in the drug layer, for example, 305, 310,315, 320, 325, 330, 335, 340, 345, 350, 355, or 360 mg polyethyleneoxide in the drug layer. In some embodiments, in conjunction with otherabove or below embodiments, the oral dosage forms disclosed hereincomprise 115.6 mg, 206 mg, 230.9 mg, 274.6 mg, 301.4 mg, 307.2 mg, 314.8mg, 332.8 mg, or 358.4 mg polyethylene oxide in the drug layer.

Diluents, Lubricants, and Glidants

In some embodiments, in conjunction with other embodiments above orbelow, the drug layer comprises a diluent. The diluent can beextragranular (EG) and/or intragranular (IG). In some embodiments, thediluent is intragranular (IG). In some embodiments, the drug layercomprises intragranular and extragranular diluent. The diluent ispresent in any suitable amount. In some embodiments, in conjunction withother above or below embodiments, the diluent is present in amount of2-7 wt % of the core tablet (e.g., 2, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5,6.0, 6.5, or 7.0 wt % of the core tablet). In some embodiments, thediluent is present in 3.0 wt % of the core tablet or 4.8 wt. % of thecore tablet.

Nonlimiting examples of diluents include lactose, sucrose, glucose,mannitol, sorbitol, calcium phosphate, calcium carbonate,microcrystalline cellulose and cellulose. An illustrative suitablediluent in the drug layer is mannitol. In embodiments, wherein thediluent comprises mannitol, the drug layer typically comprises 5-60 mgmannitol (e.g., 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 mgmannitol). For example, in various embodiments, in conjunction withother above or below embodiments, the drug layer comprises 8.1 mg, 16.2mg, 22.1 mg, 25.0 mg, 48.0 mg, 52.0 mg, or 56.0 mg mannitol. In someembodiments, the drug layer comprises 12.3 mg mannitol (IG) and 9.8 mgmannitol (EG), 9.0 mg mannitol (IG) and 7.2 mg mannitol (EG), 4.5 mgmannitol (IG) and 3.6 mg mannitol (EG), or 25 mg mannitol (IG) and 25 mgmannitol (EG). In some embodiments, the drug layer comprises 50 mgmannitol (EG). In some embodiments comprising both IG mannitol and EGmannitol, 55-57% of the total mannitol present is intragranular and43-45% of the total mannitol present is extragranular.

In some embodiments, in conjunction with other embodiments above orbelow, the drug layer comprises a lubricant. The lubricant can beextragranular (EG) and/or intragranular (IG). In some embodiments, thelubricant is intragranular (IG). In some embodiments, the drug layercomprises intragranular and extragranular lubricant. The lubricant ispresent in any suitable amount. In some embodiments, in conjunction withother above or below embodiments, example, the lubricant is present inamount of 0.05-0.50 wt % of the core tablet (e.g., 0.05, 0.10, 0.15,0.2, 0.25, 0.30, 0.35, 0.40, 0.45, or 0.50 wt % of the core tablet). Insome embodiments, in conjunction with other above or below embodiments,the lubricant (e.g., magnesium stearate) is present in amount of 0.25 wt%, 0.31 wt %, 0.33 wt %, or 0.37 wt % of the core tablet.

Examples of lubricants include magnesium stearate, talc, starch, andcellulose. An illustrative suitable lubricant is magnesium stearate. Inembodiments, wherein the lubricant comprises magnesium stearate, thedrug layer typically comprises 1-5 mg of magnesium stearate (e.g., 1.0,1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg magnesium stearate). Forexample, in various embodiments, in conjunction with other above orbelow embodiments, the drug layer comprises 1.0, 1.7, 2.0, 2.4, 2.5,2.6, 2.7, or 2.8 mg magnesium stearate. In some embodiments, the druglayer comprises 0.5, 0.9, 1.0, 1.2, 1.3, or 1.4 mg magnesium stearate(IG) and 0.5, 1.0, 1.2, 1.3, or 1.4 mg magnesium stearate (EG).

In some embodiments, in conjunction with other embodiments above orbelow, the drug layer comprises a glidant. In some embodiments, theglidant is extragranular. The glidant is present in any suitable amount.In some embodiments, in conjunction with other above or belowembodiments, example, the glidant is present in amount of 0.05-0.50 wt %of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40,0.45, or 0.50 wt % of the core tablet). In some embodiments, inconjunction with other above or below embodiments, the glidant (e.g.,colloidal silicon dioxide) is present in amount of 0.25 wt %, 0.33 wt %,0.34 wt %, or 0.37 wt % of the core tablet.

Examples of glidants include silica, magnesium stearate, and talc. Anillustrative suitable glidant is silicon dioxide (e.g., colloidalsilicon dioxide). In embodiments, wherein the glidant comprises silicondioxide, the drug layer typically comprises 0.5-5 mg silicon dioxide(e.g., 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5,or 5.0 mg silicon dioxide). For example, in various embodiments, inconjunction with other above or below embodiments, the drug layercomprises 0.9, 1.8, 2.0, 2.4, 2.5, 2.6, 2.7, or 2.8 mg silicon dioxide.

In some embodiments, the drug layer of the disclosed oral dosage formsfurther comprises an osmotic agent. When present, the osmotic agent ofthe drug layer can be any suitable osmotic agent. Nonlimiting examplesof osmotic agents include sugars and sodium chloride. In someembodiments, in conjunction with other above or below embodiments, theosmotic agent of the drug layer comprises sodium chloride. The osmoticagent of the drug layer is present in any suitable amount. In someembodiments, in conjunction with other above or below embodiments, thedrug layer comprises 2-12 wt % osmotic agent (e.g., 2, 3, 4, 5, 6, 7, 8,9, 10, 11, or 12 wt % osmotic agent). In some embodiments, the druglayer comprises 5 wt %, 7.7 wt %, or 10 wt % osmotic agent (e.g., sodiumchloride). Depending on the dosage strength of the dosage form, the druglayer comprises 15-60 mg osmotic agent (e.g., 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, or 60 mg osmotic agent). In some embodiments, the drug layercomprises 18.0, 26.7, 40, or 53.3 osmotic agent (e.g., sodium chloride).In some embodiments, the osmotic agent (e.g., sodium chloride) of thedrug layer is present in an amount of 3-8 wt % of the core tablet (e.g.,3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3,4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7,5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7.0, 7.1,7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8.0 wt % of the core tablet).In some embodiments, the osmotic agent (e.g., sodium chloride) of thedrug layer is present in an amount of 3.3 wt %, 5.1 wt %, or 6.7 wt % ofthe core tablet.

Swellable Layer

The swellable layer comprises one or more swellable polymers. As such,the swellable layer expands when in contact with water, the expansion ofwhich creates pressure which results in drug release from the drug layerthrough the at least one drug release orifice of the dosage form. Insome embodiments, in conjunction with other above or below embodiments,the drug layers and swellable layers are present in a weight ratio of2:1 in the core tablet.

The swellable polymer can be any suitable swellable polymer. In someembodiments, the swellable polymer comprises polyethylene oxide. Anillustrative suitable polyethylene oxide for the swellable layer is, forexample, POLYOX® WSR Coagulant (commercially available from Dupont;Midland, Mich.) having the following physical properties: MW of5,000,000 Da; viscosity: 5500-7500 cP; and silicon dioxide 0.8-3.0 wt %.The polyethylene oxide of the swellable layer typically has a highermolecular weight than polyethylene oxide of the drug layer (e.g.,5,000,000 Da).

The swellable polymer is present in any suitable amount. Typically, theswellable polymer is present in an amount of 50-70 wt % of the swellablelayer (e.g., polyethylene oxide) (e.g., 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, or 70 wt % of theswellable layer). In some embodiments, in conjunction with other aboveor below embodiments, the swellable polymer is present in an amount of50-70 wt %, 55-70 wt %, or 55-65 wt % of the swellable layer. In someembodiments, the swellable polymer is present in 64.8 wt %, 64.9 wt %,or 65 wt % of the swellable layer. Depending on the dosage strength ofthe dosage form, the swellable polymer is present in an amount of 50-75mg, 100-130 mg, 150-200 mg in the swellable layer. In some embodiments,the swellable polymer (e.g., polyethylene oxide) is present in an amountof 58.6 mg, 117.0 mg, 129.8 mg, 159.6 mg, or 173.1 mg in the swellablelayer. In some embodiments, the swellable polymer (e.g., polyethyleneoxide) is present in an amount of 15-25 wt % of the core tablet (e.g.,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 wt % of the core tablet).In some embodiments, the swellable polymer comprises 21.6 wt % or 22 wt% of the core tablet.

In some embodiments, the swellable layer further comprises one or moreof an osmotic agent, a diluent, a lubricant, and a colorant.

The osmotic agent of the swellable layer can be any suitable osmoticagent as described herein. Nonlimiting examples of osmotic agentsinclude sugars and sodium chloride. In some embodiments, in conjunctionwith other above or below embodiments, the osmotic agent comprisessodium chloride. The osmotic agent is present in any suitable amount. Insome embodiments, in conjunction with other above or below embodiments,the swellable layer comprises 5-15 wt % osmotic agent (e.g., 5, 6, 7, 8,9, 10, 11, 12, 13, 14, or 15 wt % osmotic agent). In some embodiments,the swellable layer comprises 5-10 wt %, 5-7 wt %, 8-12 wt %, or 8-10 wt% osmotic agent. In some embodiments, the swellable layer comprises 8.4wt %, 8.5 wt %, 8.6 wt %, 9.1 wt %, or 9.8 wt % osmotic agent. Dependingon the dosage strength of the dosage form, the swellable layer comprises5-25 mg osmotic agent (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, or 25 mg osmotic agent). In someembodiments, the swellable layer comprises 7.8 mg, 15.5 mg, 17.2 mg,20.6 mg, 21.1 mg, 22.4 mg, 22.9 mg, or 24.1 mg osmotic agent (e.g.,sodium chloride). In some embodiments, the osmotic agent (e.g., sodiumchloride) is present in an amount of 1.5-3.5 wt % of the total coretablet (e.g., 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5,2.6, 2.7, 2.8, 2.9, 3.0, 3.1, 3.2, 3.3, 3.4, or 3.5 wt % of the coretablet). In some embodiments, the osmotic agent (e.g. sodium chloride)is present in an amount of 2.80, 2.85, 2.90, or 2.95 wt % of the coretablet.

The diluent of the swellable layer can be any suitable diluent asdescribed herein. An illustrative suitable diluent in the swellablelayer is microcrystalline cellulose. In some embodiments, in conjunctionwith other above or below embodiments, the diluent comprisesmicrocrystalline cellulose. The diluent is present in any suitableamount. In some embodiments, the diluent (e.g., microcrystallinecellulose) is present in an amount of 20-35 wt % of the swellable layer(e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35wt %). In some embodiments, the diluent is present in an amount of 25.2wt %, 25.8 wt %, 27.3 wt %, or 29.4 wt % of the swellable layer. In someembodiments, the diluent is present in an amount of 7-10 wt % of thecore tablet (e.g., 7.0, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9,8.0, 8.1, 8.2, 8.3, 8.4, 8.5, 8.6, 8.7, 8.8, 8.9, 9.0, 9.1, 9.2, 9.3,9.4, 9.5, 9.6, 9.7, 9.8, 9.9, or 10.0 wt % of the core tablet).

The lubricant of the swellable layer can be any suitable lubricant asdescribed herein. An illustrative suitable lubricant in the swellablelayer is magnesium stearate. The lubricant is present in any suitableamount. In some embodiments, the lubricant is present in an amount of0.3-1 wt % of the swellable layer (e.g., 0.3, 0.4, 0.5, 0.6, 0.7, 0.8,0.9, 1.0 wt % of the swellable layer). In some embodiments, inconjunction with other above or below embodiments, the lubricant ispresent in an amount of 0.5 wt % or 0.6 wt % of the swellable layer. Insome embodiments, in conjunction with other above or below embodiments,example, the lubricant of the swellable layer is present in amount of0.05-0.50 wt % of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25,0.30, 0.35, 0.40, 0.45, or 0.50 wt % of the core tablet). Depending onthe dosage strength of the dosage form, in various embodiments, theswellable layer comprises 0.5, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, or 1.5 mgmagnesium stearate.

The coloring agent can be any suitable coloring agent. An illustrativesuitable coloring agent is iron oxide red. The coloring agent is presentin any suitable amount. In some embodiments, in conjunction with otherabove or below embodiments, example, the coloring agent (e.g., ironoxide red) of the swellable layer is present in amount of 0.05-0.50 wt %of the core tablet (e.g., 0.05, 0.10, 0.15, 0.2, 0.25, 0.30, 0.35, 0.40,0.45, or 0.50 wt % of the core tablet). In some embodiments, thecoloring agent is present in an amount of 0.05, 0.06, 0.07, 0.08, 0.09,or 0.10 wt % of the core tablet. In various embodiments, in conjunctionwith other above or below embodiments, the swellable layer comprises 0.2mg, 0.4 mg, or 0.5 mg coloring agent (e.g., iron oxide red).

Coating Layer

The oral dosage forms disclosed herein comprise a coating layer disposedon the core tablet. In some embodiments, the coating layer is present inan amount of 6.5-8.5 wt % based upon the total oral dosage form weight.In some embodiments, the coating layer is present in an amount of 7.5 wt% based upon the total oral dosage form weight. In some embodiments, thecoating layer comprises cellulose acetate (CA) and polyethylene glycol(PEG). In various embodiments, the PEG has an average molecular weightof 3,000-4,000 Da, for example, 3,000-3,700 Da, or 3,350 Da.

The cellulose acetate and PEG are present in any suitable amounts. Insome embodiments, the coating layer comprises 10-80 mg of CA (e.g., 10,20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 mg CA). In someembodiments, the coating layer comprises 15.2, 30.3, 36.3, 37.4, 40.3,41.3, 49.6, 72.0, and 74.9 mg CA. In some embodiments, in conjunctionwith other above or below embodiments, the coating layer comprises 3.8,7.6, 9.1, 9.4, 10.1, 10.3, 12.4, 18.0, or 18.7 mg PEG. In someembodiments, the CA and PEG are present in a CA:PEG weight ratio of 3.5to 4.5:1. For example, in some embodiments, the weight ratio of CA toPEG in the coating layer is 3.5, 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3,4.4, or 4.5. In some embodiments, the CA and PEG are present in a CA:PEGweight ratio of 4:1.

Sub-Coat Layer

In some embodiments, the disclosed oral dosage forms further comprise asub-coat layer between the core tablet and coating layer. In someembodiments, the sub-coat layer comprises hydroxypropyl methylcellulose(HPMC).

The sub-coat layer, when present, is present in any suitable amount. Insome embodiments, the sub-coat layer is present in an amount of 2-4 wt %of the oral dosage form (e.g., 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8,2.9, 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4.0 wt % ofthe oral dosage form). In some embodiments, the sub-coat layer ispresent in an amount of 2.3 wt % of the oral dosage form. In someembodiments, the sub-coat layer is present in an amount of 3.4 wt % ofthe oral dosage form.

In some embodiments, the coating layer further comprises a color coatlayer. The color coat layer comprises one or more suitable colorants. Anillustrative suitable colorant is the Opadry® II colorants commerciallyavailable from Colorcon, Inc. (Harleysville, Pa.). The color coat layeris present in a suitable amount. In some embodiments, the color coatlayer is present in an amount of 3-5 wt % (3.0, 3.5, 4.0, 4.5, 5.0 wt %)of the oral dosage form. In some embodiments, the color coat layer ispresent in an amount of 3.4 wt % of the oral dosage form.

Drug Release Orifice

The oral dosage forms disclosed herein comprise at least one drugrelease orifice. In some embodiments, the drug release orifice in madeby drilling the oral dosage forms. Typically, the drug release orificeranges in size from 600 μm to 1.5 mm. In some embodiments, the oraldosage forms are drilled using a 900 μm drill. In some embodiments, theoral dosage forms are drilled using a 1600 μm drill. In someembodiments, the drug release orifice has a size of 1.2 mm.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising (i) a drug layer comprising 8-11 wt% apremilast based upon total core tablet weight, 8-11 wt % hypromelloseacetate succinate (HPMCAS) based upon total core tablet weight, 2-7 wt %mannitol based upon total core tablet weight, 40-45 wt % polyethyleneoxide based upon total core tablet weight, 0.1-0.5 wt % magnesiumstearate based upon total core tablet weight, and 0.1-0.5 wt % colloidalsilicon dioxide based upon total core tablet weight, wherein theapremilast and HPMCAS are in a solid dispersion; (ii) a swellable layercomprising 18-25 wt % polyethylene oxide based upon total core tabletweight, 7-10 wt % microcrystalline cellulose based upon total coretablet weight, 1.5-3.5 wt. % sodium chloride based upon total coretablet weight, 0.01-0.2 wt % iron oxide based upon total core tabletweight, and 0.05-0.3 wt % magnesium stearate based upon total coretablet weight; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising a core tablet comprising (i) a druglayer comprising 75 mg apremilast, 75 mg hypromellose acetate succinate(HPMCAS), 22.1 mg mannitol, 314.8 mg polyethylene oxide, 2.4 mgmagnesium stearate, and 2.5 mg colloidal silicon dioxide, wherein theapremilast and HPMCAS are in a solid dispersion; (ii) a swellable layercomprising 159.6 mg polyethylene oxide, 63.4 mg microcrystallinecellulose, 21.1 mg sodium chloride, 0.5 mg iron oxide, and 1.2 mgmagnesium stearate; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising a core tablet comprising (i) a druglayer comprising 55 mg apremilast, 55 mg hypromellose acetate succinate(HPMCAS), 16.2 mg mannitol, 230.9 mg polyethylene oxide, 1.7 mgmagnesium stearate, and 1.8 mg colloidal silicon dioxide, wherein theapremilast and HPMCAS are in a solid dispersion; (ii) a swellable layercomprising 117 mg polyethylene oxide, 46.5 mg microcrystallinecellulose, 15.5 mg sodium chloride, 0.4 mg iron oxide, and 0.9 mgmagnesium stearate; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising a core tablet comprising (i) a druglayer comprising 27.5 mg apremilast, 27.5 mg hypromellose acetatesuccinate (HPMCAS), 8.1 mg mannitol, 115.6 mg polyethylene oxide, 1.0 mgmagnesium stearate, and 0.9 mg colloidal silicon dioxide, wherein theapremilast and HPMCAS are in a solid dispersion; (ii) a swellable layercomprising 58.6 mg polyethylene oxide, 23.3 mg microcrystallinecellulose, 7.8 mg sodium chloride, 0.2 mg iron oxide, and 0.5 mgmagnesium stearate; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising (i) a drug layer comprising 10-15wt. % apremilast based upon total core tablet weight, 10-15 wt %hypromellose acetate succinate (HPMCAS) based upon total core tabletweight, 30-40 wt % polyethylene oxide based upon total core tabletweight, 2-8 wt % sodium chloride based upon total core tablet weight,0.1-0.5 wt % magnesium stearate based upon total core tablet weight, and0.1-0.5 wt % colloidal silicon dioxide based upon total core tabletweight, wherein the apremilast and HPMCAS are in a solid dispersion; and(ii) a swellable layer comprising 18-25 wt % polyethylene oxide basedupon total core tablet weight, 7.5-10.0 wt % microcrystalline cellulosebased upon total core tablet weight, 2-4 wt % sodium chloride based upontotal core tablet weight, 0.01-0.1 wt % iron oxide based upon total coretablet weight, and 0.05-0.3 wt % magnesium stearate based upon totalcore tablet weight; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising a core tablet comprising (i) a druglayer comprising 100 mg apremilast, 100 mg hypromellose acetatesuccinate (HPMCAS), 301.4 mg polyethylene oxide, 26.7 mg sodiumchloride, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicondioxide, wherein the apremilast and HPMCAS are in a solid dispersion;(ii) a swellable layer comprising 173.1 mg polyethylene oxide, 68.8 mgmicrocrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide,and 1.3 mg magnesium stearate; and a coating layer disposed on the coretablet and comprising cellulose acetate and polyethylene glycol; whereinthe oral dosage form surface comprising at least one drug releaseorifice.

In some embodiments, the disclosure provides oral dosage formscomprising a core tablet comprising a core tablet comprising (i) a druglayer comprising 100 mg apremilast, 100 mg hypromellose acetatesuccinate (HPMCAS), 274.6 mg polyethylene oxide, 53.3 sodium chloride,2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, whereinthe apremilast and HPMCAS are in a solid dispersion; (ii) a swellablelayer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystallinecellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mgmagnesium stearate; and a coating layer disposed on the core tablet andcomprising cellulose acetate and polyethylene glycol; wherein the oraldosage form surface comprising at least one drug release orifice.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 60 mgapremilast, 60 mg hypromellose acetate succinate (HPMCAS), 48 mgmannitol, 307.2 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.4 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; and (ii) a swellable layer comprising 155.8 mgpolyethylene oxide, 61.9 mg microcrystalline cellulose, 20.6 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) acoating layer comprising 37.4 mg CA and 9.4 mg PEG, wherein the oraldrug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 60 mgapremilast, 60 mg hypromellose acetate succinate (HPMCAS), 48 mgmannitol, 307.2 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.4 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 155.8 mgpolyethylene oxide, 61.9 mg microcrystalline cellulose, 20.6 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) acoating layer comprising 72.0 mg CA and 18.0 mg PEG, wherein the oraldrug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 65 mgapremilast, 65 mg hypromellose acetate succinate (HPMCAS), 52 mgmannitol, 332.8 mg polyethylene oxide, 2.6 mg magnesium stearate, and2.6 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 168.7 mgpolyethylene oxide, 67.1 mg microcrystalline cellulose, 22.4 mg sodiumchloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) acoating layer comprising 37.4 mg CA and 9.4 mg PEG, wherein the oraldrug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 65 mgapremilast, 65 mg hypromellose acetate succinate (HPMCAS), 52 mgmannitol, 332.8 mg polyethylene oxide, 2.6 mg magnesium stearate, and2.6 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 168.7 mg ofpolyethylene oxide, 67.1 mg microcrystalline cellulose, 22.4 mg sodiumchloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) acoating layer comprising 74.9 mg CA and 18.7 mg PEG, wherein the oraldrug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 70 mgapremilast, 70 mg hypromellose acetate succinate (HPMCAS), 56 mgmannitol, 358.4 mg polyethylene oxide, 2.8 mg magnesium stearate, and2.8 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 181.7 mgpolyethylene oxide, 72.3 mg microcrystalline cellulose, 24.1 mg sodiumchloride, 0.5 mg iron oxide, and 1.4 mg magnesium stearate; and b) acoating layer comprising 40.3 mg CA and 10.1 mg PEG, wherein the oraldrug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mgmannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 159.6 mgpolyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; b) a subcoatlayer comprising 18.4 mg HPMC; and c) a coating layer comprising 36.3 mgCA and 9.1 mg PEG, wherein the oral drug dosage form comprises at leastone drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mgmannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 159.6 mgpolyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; b) a subcoatlayer comprising 18.4 mg HPMC; and c) a coating layer comprising 49.6 mgCA and 12.4 mg PEG, wherein the oral drug dosage form comprises at leastone drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mgmannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 159.6 mgpolyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; b) a coatinglayer comprising 41.3 mg CA and 10.3 mg PEG, wherein the coating layerfurther comprises 27.6 mg of a colorant, wherein the oral drug dosageform comprises at least one drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 22.1 mgmannitol, 314.8 mg polyethylene oxide, 2.4 mg magnesium stearate, and2.5 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 159.6 mgpolyethylene oxide, 63.4 mg microcrystalline cellulose, 21.1 mg sodiumchloride, 0.5 mg iron oxide, and 1.2 mg magnesium stearate; and b) acoating layer comprising 41.3 mg CA and 10.3 mg PEG, wherein coatinglayer further comprises 27.6 mg of colorant and the oral drug dosageform comprises at least one drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 55 mgapremilast, 55 mg hypromellose acetate succinate (HPMCAS), 16.2 mgmannitol, 230.9 mg polyethylene oxide, 1.7 mg magnesium stearate, and1.8 mg colloidal silicon dioxide, wherein the apremilast and HPMCAS arein a solid dispersion; (ii) a swellable layer comprising 117 mgpolyethylene oxide, 46.5 mg microcrystalline cellulose, 15.5 mg sodiumchloride, 0.4 mg iron oxide, and 0.9 mg magnesium stearate; and b) acoating layer comprising 30.3 mg CA and 7.6 mg PEG, wherein coatinglayer further comprises 20.2 mg of colorant and the oral drug dosageform comprises at least one drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 27.5mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 8.1 mgmannitol, 115.6 mg polyethylene oxide, 1 mg magnesium stearate, and 0.9mg colloidal silicon dioxide, wherein the apremilast and HPMCAS are in asolid dispersion; (ii) a swellable layer comprising 58.6 mg polyethyleneoxide, 23.3 mg microcrystalline cellulose, 7.8 mg sodium chloride, 0.2mg iron oxide, and 0.5 mg magnesium stearate; and b) a coating layercomprising 15.2 mg CA and 3.8 mg PEG, wherein coating layer furthercomprises 10.1 mg of colorant and the oral drug dosage form comprises atleast one drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 100 mgapremilast, 100 mg hypromellose acetate succinate (HPMCAS), 26.7 mgsodium chloride, 150.7 mg polyethylene oxide having a MW of 300,000 Da,150.7 mg polyethylene oxide having a MW of 200,000, 2.6 mg magnesiumstearate, and 2.7 mg colloidal silicon dioxide, wherein the apremilastand HPMCAS are in a solid dispersion; (ii) a swellable layer comprising173.1 mg polyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mgsodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; andb) a coating layer as described herein, wherein the oral drug dosageform comprises at least one drug release orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 100 mgapremilast, 100 mg hypromellose acetate succinate (HPMCAS), 53.3 mgsodium chloride, 274.6 mg polyethylene oxide having a MW of 300,000 Da,2.6 mg magnesium stearate, and 2.7 mg colloidal silicon dioxide, whereinthe apremilast and HPMCAS are in a solid dispersion; (ii) a swellablelayer comprising 173.1 mg polyethylene oxide, 68.8 mg microcrystallinecellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mgmagnesium stearate; and b) a coating layer as described herein, whereinthe oral drug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodiumchloride, 206 mg polyethylene oxide having a MW of 300,000 Da, 2 mgmagnesium stearate, and 2 mg colloidal silicon dioxide, wherein theapremilast and HPMCAS are in a solid dispersion; (ii) a swellable layercomprising 129.8 mg polyethylene oxide, 51.6 mg microcrystallinecellulose, 17.2 mg sodium chloride, 0.4 mg iron oxide, and 1 mgmagnesium stearate; and b) a coating layer as described herein, whereinthe oral drug dosage form comprises at least one drug release orifice asdescribed herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodiumchloride, 274.6 mg polyethylene oxide having a MW of 300,000 Da, 2 mgmagnesium stearate, 50 mg mannitol, and 2 mg colloidal silicon dioxide,wherein the apremilast and HPMCAS are in a solid dispersion; (ii) aswellable layer comprising 173.1 mg polyethylene oxide, 68.8 mgmicrocrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide,and 1.3 mg magnesium stearate; and b) a coating layer as describedherein, wherein the oral drug dosage form comprises at least one drugrelease orifice as described herein.

In some embodiments, the disclosure provides an oral dosage formcomprising a) a core table comprising (i) a drug layer comprising 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 40 mg sodiumchloride, 274.6 mg polyethylene oxide having a MW of 300,000 Da, 2 mgmagnesium stearate, 25 mg mannitol (IG), 25 mg mannitol (EG), and 2 mgcolloidal silicon dioxide, wherein the apremilast and HPMCAS are in asolid dispersion; (ii) a swellable layer comprising 173.1 mgpolyethylene oxide, 68.8 mg microcrystalline cellulose, 22.9 mg sodiumchloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate; and b) acoating layer as described herein, wherein the oral drug dosage formcomprises at least one drug release orifice as described herein.

Methods of Treating

The disclosure provides methods of treating a patient suffering from adisease or disorder ameliorated by inhibiting PDE4 comprisingadministering to the patient under fed conditions the oral dosage formsdisclosed herein.

A subject in a fed state refers to a subject who has taken food or hashad a meal. In some embodiments, the formulation disclosed herein isadministered to a subject in a fed state 5 minutes post-meal, 10 minutespost-meal, 15 minutes post-meal, 20 minutes post-meal, 30 minutespost-meal, 40 minutes post-meal, 50 minutes post-meal, 1 hour post-meal,or 2 hours post-meal. In some cases, a formulation as disclosed hereinis administered to a subject in a fed state 30 minutes post-meal. Invarious cases, a formulation as disclosed herein is administered to asubject in a fed state 1 hour post-meal. In some embodiments, aformulation as disclosed herein is administered to a subject with food.

In some embodiments, the disease or disorder is asthma, arthritis,psoriasis, inflammation, chronic or acute obstructive pulmonarydiseases, chronic or acute pulmonary inflammatory diseases, cutaneouslupus erythematosis, inflammatory bowel disease, Crohn's Disease,Behcet's Disease, hidradenitis suppurativa, or colitis. In someembodiments, the disease or disorder arthritis. In some embodiments, thearthritis is psoriatic arthritis. In some embodiments, the disease ordisorder is psoriasis. In some embodiments, the disease or disorder iscolitis. In some embodiments, the colitis is ulcerative colitis. In someembodiments, the disease or disorder is Behcet's disease. In someembodiments, the disease or disorder is inflammatory bowel disease. Insome embodiments, the disease or disorder is hidradenitis suppurativa.

In some embodiments, the disclosed oral dosage forms are administeredafter an initial titration with a conventional twice-a-day apremilastformulation.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; (iv) 20 mg in the morning and20 mg after noon on the fourth day of administration; (v) 20 mg in themorning and 30 mg after noon on the fifth day of administration; and(vi) 30 mg in the morning and 30 mg after noon on days 6-14 ofadministration; and the disclosed oral dosage form once daily everysubsequent day of administration. In some embodiments, the oral dosageform administered on day 15 and thereafter comprises 27.5 mg apremilast,55 mg apremilast, or 75 mg apremilast.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; (iv) 20 mg in the morning and20 mg after noon on the fourth day of administration; (v) 20 mg in themorning and 30 mg after noon on the fifth day of administration; and(vi) 30 mg in the morning and 30 mg after noon on Days 6-14 ofadministration; and a disclosed oral dosage form having 75 mg apremilastonce daily in the morning Day 15 and every subsequent day ofadministration.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; (iv) 20 mg in the morning and20 mg after noon on the fourth day of administration; (v) 20 mg in themorning and 30 mg after noon on the fifth day of administration; and(vi) an oral dosage form as disclosed herein having 75 mg apremilastonce daily in the morning Day 6 and thereafter.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; and (iv) an oral dosage form asdisclosed herein having 55 mg apremilast once daily in the morning Day 4and thereafter.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; (iv) 20 mg in the morning and20 mg after noon on Day 4 to Day 14; and (v) an oral dosage form asdisclosed herein having 55 mg apremilast once daily in the morning Day15 and thereafter.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; and (iv) two oral dosage formsas disclosed herein having 27.5 mg apremilast (for a total of 55 mgapremilast) once daily in the morning Day 4 and thereafter.

In some embodiments, the disclosed method comprises the followinginitial titration schedule: (i) 10 mg in the morning on the first day ofadministration; (ii) 10 mg in the morning and 10 mg after noon on thesecond day of administration; (iii) 10 mg in the morning and 20 mg afternoon on the third day of administration; (iv) 20 mg in the morning and20 mg after noon on Day 4 to Day 14; and (v) two oral dosage forms asdisclosed herein having 27.5 mg apremilast (for a total of 55 mgapremilast) once daily in the morning Day 15 and thereafter.

EMBODIMENTS

1. An oral dosage form comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising apremilast and hypromellose            acetate succinate (HPMCAS) in an amorphous solid dispersion;            and        -   (ii) a swellable layer comprising one or more swellable            polymers; and    -   b. a coating layer disposed on the core tablet, wherein the oral        dosage form surface comprises at least one drug release orifice.

2. The oral dosage form of embodiment 1, wherein the apremilast ispresent in an amount of 6-15 wt % of the core tablet.

3. The oral dosage form of embodiment 1 or 2, wherein the soliddispersion is spray-dried.

4. The oral dosage form of any one of embodiments 1-3, wherein theHPMCAS is present in an amount of 6-15 wt % of the core tablet.

5. The oral dosage form of any one of embodiments 1-4, whereinapremilast and HPMCAS are present in a weight ratio of 45:55 to 55:45 inthe core tablet.

6. The oral dosage form of embodiment 5, wherein apremilast and HPMCASare present in a weight ratio of 48:52 to 52:48.

7. The oral dosage form of embodiment 5, wherein apremilast and HPMCASare present in a weight ratio of 50:50.

8. The oral dosage form of any one of embodiments 1-7, wherein the druglayer further comprises one or more of a water soluble polymer, adiluent, an osmotic agent, and a lubricant.

9. The oral dosage form of embodiment 8, wherein the water solublepolymer is present in an amount of 30-55 wt % of the core tablet.

10. The oral dosage form of embodiment 8 or 9, wherein the water solublepolymer comprises polyethylene oxide.

11. The oral dosage form of embodiment 10, wherein the polyethyleneoxide has an average molecular weight of 200,000-600,000 Da.

12. The oral dosage form of embodiment 11, wherein the drug layercomprises polyethylene oxide having an average molecular weight of200,000 Da.

13. The oral dosage form of embodiment 11, wherein the drug layercomprises polyethylene oxide having an average molecular weight of300,000 Da.

14. The oral dosage form of embodiment 11, wherein the drug layercomprises polyethylene oxide having an average molecular weight of600,000 Da.

15. The oral dosage form of any one of embodiments 8-14, wherein thewater soluble polymer and apremilast are present in a weight ratio of 2to 6:1, in the drug layer.

16. The oral dosage form of any one of embodiments 8-15, wherein thediluent comprises mannitol.

17. The oral dosage form of any one of embodiments 8-16, wherein thediluent is present in an amount of 2-7 wt % of the core tablet.

18. The oral dosage form of any one of embodiments 8-17, wherein thedrug layer comprises intragranular diluent and extragranular diluent.

19. The oral dosage form of any one of embodiment 8-18, wherein theosmotic agent is present in the drug layer in an amount of 3-8 wt % ofthe core tablet.

20. The oral dosage form of any one of embodiments 8-19, wherein theosmotic agent in the drug layer comprises sodium chloride.

21. The oral dosage form of any one of embodiments 8-20, wherein thelubricant comprises magnesium stearate.

22. The oral dosage form of any one of embodiments 8-21, wherein thelubricant of the drug layer is present in an amount of 0.05-0.5 wt % ofthe core tablet.

23. The oral dosage form of any one of embodiments 1-22, wherein thedrug layer further comprises extragranular glidant, extragranularlubricant, or both.

24. The oral dosage form of embodiment 23, wherein the extragranularglidant comprises silicon dioxide.

25. The oral dosage form of embodiment 23 or 24, wherein theextragranular lubricant comprises magnesium stearate.

26. The oral dosage form of any one of embodiments 1-25, wherein thedrug layer and swellable layer are present in a weight ratio of 2:1 inthe core tablet.

27. The oral dosage form of any one embodiments 1-26, wherein theswellable polymer comprises polyethylene oxide.

28. The oral dosage form of embodiment 27, wherein the polyethyleneoxide has an average molecular weight of 5,000,000 Da.

29. The oral dosage form of any one of embodiments 1-28, wherein theswellable layer further comprises one or more of an osmotic agent, adiluent, a lubricant, and a colorant.

30. The oral dosage form of embodiment 29, wherein the osmotic agent ofthe swellable layer comprises sodium chloride.

31. The oral dosage form of embodiment 29 or 30, wherein the osmoticagent in the swellable layer is present in an amount of 2.5-3.5 wt % ofthe core tablet.

32. The oral dosage form of any one of embodiments 29-31, wherein thediluent of the swellable layer comprises microcrystalline cellulose.

33. The oral dosage form of any one of embodiments 29-32, wherein thediluent in the swellable layer is present in an amount of 7-10 wt % ofthe core tablet.

34. The oral dosage form of any one of embodiments 29-33, wherein thelubricant of the swellable layer comprises magnesium stearate.

35. The oral dosage form of any one of embodiments 29-34, where thelubricant of the swellable layer is present in an amount of 0.05-0.5 wt% of the core tablet.

36. The oral dosage form of any one of embodiments 29-35, wherein thecolorant comprises iron oxide red.

37. The oral dosage form of any one of embodiments 29-36, where thecolorant is present in an amount of 0.05-0.5 wt % of the core tablet.

38. The oral dosage form of any one of embodiments 1-37, wherein thecoating comprises cellulose acetate and polyethylene glycol.

39. The oral dosage form of embodiment 38, wherein the cellulose acetateand polyethylene glycol are present in a weight ratio 3.5 to 4.5:1 inthe coating.

40. The oral dosage form of any one of embodiments 1-39, wherein thecoating comprises 6.5-8.5 wt % of the total weight of the oral dosageform.

41. The oral dosage form of embodiment 40, wherein the coating comprises7.5 wt % of the total weight of the oral dosage form.

42. The oral dosage form of any one of embodiments 1-41, furthercomprising a sub-coat layer between the core tablet and the coatinglayer.

43. The oral dosage form of embodiment 42, wherein the sub-coat layercomprises hydroxypropyl methylcellulose.

44. The oral dosage form of embodiment 42 or 43, wherein the sub-coatlayer is present in an amount of 2-4 wt % of the oral dosage form.

45. The oral dosage form of embodiment 44, wherein the sub-coat layer ispresent in an amount of 2.3 wt % of the oral dosage form.

46. The oral dosage form of embodiment 44, wherein the sub-coat layer ispresent in an amount of 3.4 wt % of the oral dosage form.

47. The oral dosage form of any one of embodiments 1-46, wherein thedrug layer comprises an intragranular portion and an extragranularportion.

48. The oral dosage form of embodiment 47, wherein the extragranularportion comprises a lubricant and a glidant.

49. The oral dosage form of embodiment 48, wherein the extragranularportion further comprises a diluent.

50. The oral dosage form of embodiment 49, wherein the lubricantcomprises magnesium stearate, the glidant comprises silicon dioxide, andthe diluent comprises mannitol.

51. The oral dosage form of any one of embodiments 47-50, wherein theintragranular portion comprises apremilast, HPMCAS, polyethylene oxide,and mannitol, and an intragranular lubricant.

52. The oral dosage form of embodiment 51, wherein the intragranularlubricant comprises magnesium stearate.

53. The oral dosage form of any one of embodiments 49-52, wherein themannitol is present in both the intragranular portion and theextragranular portion.

54. The oral dosage form of embodiment 53, comprising 55-57% of thetotal mannitol present is in the intragranular portion and 43-45% of thetotal mannitol present is in the extragranular portion.

55. The oral dose form of any one of embodiments 47-54, wherein theswellable layer further comprises a lubricant.

56. The oral dosage form of embodiment 55, wherein the lubricant of theswellable layer comprises magnesium stearate.

57. The oral dosage form of any one of embodiments 47-56, wherein thedrug layer intragranular portion comprises sodium chloride.

58. The oral dosage form of any one of embodiments 47-57, furthercomprising a color coat layer in an amount of 3-5 wt % of the oraldosage form.

59. The oral dosage form of embodiment 58, wherein the color coat layeris present in an amount of 3.4 wt % of the oral dosage form.

60. An oral dosage form comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 8-11 wt % apremilast based upon            total core tablet weight, 8-11 wt % hypromellose acetate            succinate (HPMCAS) based upon total core tablet weight, 2-7            wt % mannitol based upon total core tablet weight, 40-45 wt            % polyethylene oxide with molecular weight of 200,000 Da            based upon total core tablet weight, 0.1-0.5 wt % magnesium            stearate based upon total core tablet weight, and 0.1-0.5 wt            % colloidal silicon dioxide based upon total core tablet            weight, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 18-25 wt % polyethylene            oxide with molecular weight of 5,000,000 Da based upon total            core tablet weight, 7-10 wt % microcrystalline cellulose            based upon total core tablet weight, 1.5-3.5 wt. % sodium            chloride based upon total core tablet weight, 0.01-0.2 wt %            iron oxide based upon total core tablet weight, and 0.05-0.3            wt % magnesium stearate based upon total core tablet weight;            and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

61. The oral dosage form of embodiment 60 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 75 mg apremilast, 75 mg            hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol,            314.8 mg polyethylene oxide with molecular weight of 200,000            Da, 2.4 mg magnesium stearate, and 2.5 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 159.6 mg polyethylene            oxide with molecular weight of 5,000,000 Da, 63.4 mg            microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mg            iron oxide, and 1.2 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

62. The oral dosage form of embodiment 60 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 55 mg apremilast, 55 mg            hypromellose acetate succinate (HPMCAS), 16.2 mg mannitol,            230.9 mg polyethylene oxide with molecular weight of 200,000            Da, 1.7 mg magnesium stearate, and 1.8 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 117 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 46.5 mg            microcrystalline cellulose, 15.5 mg sodium chloride, 0.4 mg            iron oxide, and 0.9 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

63. The oral dosage form of embodiment 60 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg            hypromellose acetate succinate (HPMCAS), 8.1 mg mannitol,            115.6 mg polyethylene oxide with molecular weight of 200,000            Da, 1.0 mg magnesium stearate, and 0.9 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 58.6 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 23.3 mg            microcrystalline cellulose, 7.8 mg sodium chloride, 0.2 mg            iron oxide, and 0.5 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

64. An oral dosage form comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 9-15 wt. % apremilast based upon            total core tablet weight, 10-15 wt % hypromellose acetate            succinate (HPMCAS) based upon total core tablet weight, 0-27            wt % mannitol based upon total core tablet weight, 30-40 wt            % polyethylene oxide with molecular weight of 200,000 to            300,000 Da or a mixture thereof based upon total core tablet            weight, 2-8 wt % sodium chloride based upon total core            tablet weight, 0.1-0.5 wt % magnesium stearate based upon            total core tablet weight, and 0.1-0.5 wt % colloidal silicon            dioxide based upon total core tablet weight, wherein the            apremilast and HPMCAS are in a solid dispersion;        -   (ii) a swellable layer comprising 15-25 wt % polyethylene            oxide with molecular weight of 5,000,000 Da based upon total            core tablet weight, 5-10.0 wt % microcrystalline cellulose            based upon total core tablet weight, 2-4 wt % sodium            chloride based upon total core tablet weight, 0.01-0.1 wt %            iron oxide based upon total core tablet weight, and 0.05-0.3            wt % magnesium stearate based upon total core tablet weight;            and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

65. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 100 mg apremilast, 100 mg            hypromellose acetate succinate (HPMCAS), 301.4 mg            polyethylene oxide with molecular weight of 200,000 to            300,000 Da or a mixture thereof, 26.7 mg sodium chloride,            2.6 mg magnesium stearate, and 2.7 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 173.1 mg polyethylene            oxide with molecular weight of 5,000,000 Da, 68.8 mg            microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg            iron oxide, and 1.3 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

66. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 100 mg apremilast, 100 mg            hypromellose acetate succinate (HPMCAS), 274.6 mg            polyethylene oxide with molecular weight of 300,000 Da, 53.3            sodium chloride, 2.6 mg magnesium stearate, and 2.7 mg            colloidal silicon dioxide, wherein the apremilast and HPMCAS            are in a solid dispersion;        -   (ii) a swellable layer comprising 173.1 mg polyethylene            oxide with molecular weight of 5,000,000 Da, 68.8 mg            microcrystalline cellulose, 22.9 mg sodium chloride, 0.5 mg            iron oxide, and 1.3 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

67. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 75 mg apremilast, 75 mg            hypromellose acetate succinate (HPMCAS), 226.0 mg            polyethylene oxide with molecular weight of 200,000 to            300,000 Da or a mixture thereof, 20.0 mg sodium chloride,            2.0 mg magnesium stearate, and 2.0 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 129.8 mg polyethylene            oxide with molecular weight of 5,000,000 Da, 51.6 mg            microcrystalline cellulose, 17.2 mg sodium chloride, 0.4 mg            iron oxide, and 1.0 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

68. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 75 mg apremilast, 75 mg            hypromellose acetate succinate (HPMCAS), 206.0 mg            polyethylene oxide with molecular weight of 300,000 Da, 40.0            mg sodium chloride, 2.0 mg magnesium stearate, and 2.0 mg            colloidal silicon dioxide, wherein the apremilast and HPMCAS            are in a solid dispersion;        -   (ii) a swellable layer comprising 129.8 mg polyethylene            oxide with molecular weight of 5,000,000 Da, 51.6 mg            microcrystalline cellulose, 17.2 mg sodium chloride, 0.4 mg            iron oxide, and 1.0 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

69. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 55 mg apremilast, 55 mg            hypromellose acetate succinate (HPMCAS), 165.7 mg            polyethylene oxide with molecular weight of 200,000 to            300,000 Da or a mixture thereof, 14.7 mg sodium chloride,            1.4 mg magnesium stearate, and 1.5 mg colloidal silicon            dioxide, wherein the apremilast and HPMCAS are in a solid            dispersion;        -   (ii) a swellable layer comprising 95.2 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 37.8 mg            microcrystalline cellulose, 12.6 mg sodium chloride, 0.3 mg            iron oxide, and 0.7 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release        orifice. 70. The oral dosage form of embodiment 64 comprising:    -   a. a core tablet comprising        -   (i) a drug layer comprising 55 mg apremilast, 55 mg            hypromellose acetate succinate (HPMCAS), 151.1 mg            polyethylene oxide with molecular weight of 300,000 Da, 29.3            mg sodium chloride, 1.4 mg magnesium stearate, and 1.5 mg            colloidal silicon dioxide, wherein the apremilast and HPMCAS            are in a solid dispersion;        -   (ii) a swellable layer comprising 95.2 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 37.8 mg            microcrystalline cellulose, 12.6 mg sodium chloride, 0.3 mg            iron oxide, and 0.7 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

71. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg            hypromellose acetate succinate (HPMCAS), 82.9 mg            polyethylene oxide with molecular weight of 200,000 to            300,000 Da or a mixture thereof, 7.3 mg sodium chloride, 0.8            mg magnesium stearate, and 0.7 mg colloidal silicon dioxide,            wherein the apremilast and HPMCAS are in a solid dispersion;        -   (ii) a swellable layer comprising 47.6 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 18.9 mg            microcrystalline cellulose, 6.3 mg sodium chloride, 0.1 mg            iron oxide, and 0.4 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

72. The oral dosage form of embodiment 64 comprising:

-   -   a. a core tablet comprising        -   (i) a drug layer comprising 27.5 mg apremilast, 27.5 mg            hypromellose acetate succinate (HPMCAS), 75.5 mg            polyethylene oxide with molecular weight of 300,000 Da, 14.7            mg sodium chloride, 0.4 mg magnesium stearate, and 0.7 mg            colloidal silicon dioxide, wherein the apremilast and HPMCAS            are in a solid dispersion;        -   (ii) a swellable layer comprising 47.6 mg polyethylene oxide            with molecular weight of 5,000,000 Da, 18.9 mg            microcrystalline cellulose, 6.3 mg sodium chloride, 0.1 mg            iron oxide, and 0.4 mg magnesium stearate; and    -   b. a coating layer disposed on the core tablet and comprising        cellulose acetate and polyethylene glycol; wherein the oral        dosage form surface comprises at least one drug release orifice.

73. A method of treating a patient suffering from a disease or disorderameliorated by inhibiting PDE4 comprising administering to the patientthe oral dosage form of any one of embodiments 1-72 once daily under fedconditions.

74. The method of embodiment 73, wherein the disease or disorder ispsoriasis, psoriatic arthritis, or Behcet's disease.

75. The method of embodiment 73, wherein the disease or disorder iscolitis, inflammatory bowel disease, or hidradenitis suppurativa.

76. The method of embodiment 75, wherein the disease or disorder iscolitis.

77. The method of embodiment 76, wherein the colitis is ulcerativecolitis.

78. The method of embodiment 75, wherein the disease or disorder isinflammatory bowel disease.

79. The method of embodiment 75, wherein the disease or disorder ishidradenitis suppurativa.

EXAMPLES

The following examples further illustrate the disclosed methods oftreatment, but of course, should not be construed as in any way limitingits scope.

The following abbreviations are used in the Examples: SCT refers toswellable core technology; TAB refers to tablet; SDD refers to amorphousspray-dried dispersion; APR refers to amorphous apremilast; HPMCASrefers to hypromellose acetate succinate; HPMC refers to hydroxypropylmethylcellulose; DL refers to drug layer; SL refers to swellable layer;CL refers to coating layer; PEO refers to polyethylene oxide; PEG refersto polyethylene glycol; Mg refers to magnesium; IG refers tointragranular; EG refers to extragranular; MCC refers tomicrocrystalline cellulose; NaCl refers to sodium chloride; MW refers tomolecular weight; cSiO₂ refers to colloidal silicon dioxide; CA refersto cellulose acetate; RR refers to release rate; SRC refers to standardround concave; SEM refers to scanning electron microscopy, inWC refersto inches of water column; AUC_(0-∞) refers to area under the plasmaconcentration-time curve calculated from time zero to infinity;AUC_(0-t) refers to area under the concentration-time curve calculatedfrom time zero to the last measured time point; CL/F refers to apparentclearance of drug from plasma after extravascular administration;C_(max) refers to observed maximum concentration; C_(trough) refers toobserved plasma concentration at the end of the dosing interval; Clrefers to confidence interval; CV % refers to coefficient of variation;t_(1/2) refers to terminal elimination half-life; t_(lag) refers todelay between time of administration and start of absorption lag time;T_(max) ax refers to time to C_(max); Vz/F refers to apparent volume ofdistribution during the terminal phase; F_(rel1), refers to relativebioavailability of each test formulation compared to the referenceformulation; F_(rel2) refers to relative bioavailability of eachdose-normalized test formulation compared to the dose-normalizedreference formulation IR tablet; and RA refers to ratio of accumulationbased on Day 1 and Day 5 area under the plasma concentration-time curveduring a 24-hour period.

Example 1

This example demonstrates the preparation of amorphous spray-dried soliddispersions comprising 48 wt % and 52 wt % apremilast loading weremanufactured using a PSD-1 scale spray dryer at a batch size of 2 kg foreach loading.

Solutions were prepared at 48:52 APR:HPMCAS-LG and 52:48 APR:HPMCAS-LGat 12% total solids in acetone (Tables 1 and 2). The solutions weresprayed in order of increasing drug loading, with a minor cleanperformed between the two sprays (e.g., rinsing out the chamber and ductwork with water and detergent (e.g., alkaline detergent; CIP-100), andflushing with acetone through the feed pump). Drying kinetics andthermodynamics were kept consistent with historical 50% apremilast SDDruns. The 48% drug loading in SDD had a wet yield of 82%, followed by a67% wet yield for the 52% drug loading SDD. Wet yields were calculatedfrom total net weight collected from the spray dryer, not-includingstartup/shut down quantities and pre wet SDD sampling, and based on theingoing 2 kg of solids. The averaged run conditions and wet yields forboth SDD batches are listed in Table 3.

TABLE 1 48:52 APR:HPMCAS-LG SDD 48:52 APR:HPMCAS-LG at 12 wt % Solids inAcetone Ingredient % of Blend mg/g in SDD apremilast 5.76 480.0HPMCAS-LG 6.24 520.0 Acetone 88.00 0.0

TABLE 2 52:48 APR:HPMCAS-LG SDD 52:48 APR:HPMCAS-LG at 12 wt % Solids inAcetone Ingredient % of Blend mg/g SDD apremilast  6.24 520.0 HPMCAS-LG 5.76 480.0 Acetone 88.00  0.0

TABLE 3 Run Condition Averages and Wet Yield for 48% And 52% APR SDD48:52 APR: 48:52 APR: SDD Composition HPMCAS-LG HPMCAS-LG N₂ Flow Rate(g/min) 1850 1854 Solution Flow Rate (g/min)  201  200 AtomizationPressure (psi)  496  517 Inlet Temp (° C.)  106  106 Outlet Temp (° C.) 41  41 Cyclone Pressure Differential (inWC)  11  11 Filter DP (inWC)  5   5 Wet Yield  82%  67%

Once all wet SDD samples were collected, bulk SDD from both drugloadings were secondary dried using a convection tray dryer at 40° C.and 15% relative humidity (RH). The 48% APR SDD was dried for 1100minutes and the 52% APR SDD was dried for 505 minutes. The dry yield forthe 48% and 52% drug loading SDDs were 78% and 64%, respectively, ascalculated from total net weight collected from the tray dryer,including dry SDD samples as well as wet SDD samples assuming a 5%solvent loss, and based on the 2 kg of ingoing solids.

Dry SDD from each drug loading was then characterized for particle sizedistribution using laser diffraction with a Malvern Mastersizer 2000(Malvern Panalytical; Malvern, United Kingdom). The average particlesize data are shown in Table 4. Both drug loadings had the same particlesize of 33 μm (D[4,3]), indicating that the slight difference incomposition does not impact particle size.

TABLE 4 Particle Size Data for 48% and 52% Apremilast SDD. Averages D(v0.1) D(v 0.5) D(v 0.9) D[3,2] D[4,3] Sample μm μm μm μm μm Span 48:52APR:HPMCAS-LG Dry SDD 8 30 63 13 33 1.9 52:48 APR:HPMCAS-LG Dry SDD 7 2964 13 33 2.0 *values Obtained Using a Dispersive Air Pressure of 1 Barand a Vibration Feed Rate of 65%

Characterization of the SDDs is summarized in Table 5 and includesresidual acetone by gas chromatography (GC), crystallinity by powderX-ray diffraction (PXRD), thermal properties by modulated differentialscanning calorimetry (mDSC), assay and related substances by highperformance liquid chromatography (HPLC), performance by microcentrifugedissolution and morphology by scanning electron microscopy (SEM).

TABLE 5 Physical Characterization for 48% and 52% Apremilast SDD 48:52APR: 52:48 APR: SDD Composition HPMCAS-LG HPMCAS-LG Residual AcetoneBefore Secondary Drying 3.7 wt % 3.8 wt % Residual Acetone AfterSecondary Drying 0.07 wt % 0.17 wt % Residual Water After SecondaryDrying (KF) 0.81 wt %, 6.0% RSD 0.72 wt %, 4.7% RSD Appearance by SEMSmooth collapsed and Smooth collapsed and uncollapsed spheres, nouncollapsed spheres, no evidence of crystals evidence of crystalsCrystallinity by PXRD None Detected None Detected Glass TransitionTemperature by mDSC 79.7° C. 80.5° C. Assay by HPLC (wt % APR) 47.1 wt %50.8 wt % Related Substances None Detected None Detected MicrocentrifugeDissolution C_(maxSIF1200) = 504 μg/mL, C_(maxSIF1200) = 479 μg/mL,AUC_(SIF) = 43,180 min* μg/mL AUC_(SIF) = 40,780 min* μg/mL

As shown in Table 5, there was no significant difference in residualacetone content of the 48% and 52% APR SDDs after spray drying andbefore secondary drying. The 52% APR SDD had slightly higher residualacetone after secondary drying due to a shorter drying time, but bothbatches were below the ICH limit of 5000 ppm. The 48% APR SDD was driedfor 1100 minutes and the 52% APR SDD was dried for 505 minutes.Similarly, there was no measurable difference in the glass transitiontemperatures.

SEM analysis showed both the 48% and 52% APR SDD consisting of smoothcollapsed and uncollapsed spheres, with no evidence of crystallinity.The 52% APR SDD appeared to have a greater number of uncollapsed spherescompared to the 48% APR SDD, as well as a greater number of brokenparticles.

SDD Stability Studies—Wet SDD Hold Time Study

A 48% and a 52% drug loading (by weight) SDD were manufactured using aPSD-1 scale spray dryer as described herein. Wet SDD from each batch wasstored in LDPE bags inside air-tight stainless steel containers and heldat 27° C. for up to 30 days. At 10, 20 and 30 days, samples were removedfrom each batch for characterization by SEM, mDSC, PXRD, assay andrelated substances by HPLC, residual solvent and non-sink dissolution(Microcentrifuge Dissolution Test).

SEM analysis showed both the 48% and 52% APR SDDs contain smoothcollapsed and un-collapsed spheres, with no evidence of fusing orcrystallinity. No changes in morphology or physical state were observedafter 30 days storage before secondary drying. PXRD analysis showed thatno crystallization occurred throughout the 30 day stability study forboth the 48% and 52% APR SDDs. Moreover, no morphological changesindicating crystallization were observed within the capability of themethod of SEM analysis. The DSC thermograms indicated no measurabledifference in the Tg of the stability samples compared to the dry SDD.Assay and related substances showed no increase in impurities over the30 day stability hold. Similarly, the microcentrifuge dissolutionresults showed no differences in performance over the 30 days

Example 2

This example demonstrates tablet dosage forms in accordance withembodiments of the disclosure.

Fourteen apremilast SCT dosage formulations were prepared using the 8drug layers (DL) and 6 swellable layers (SL) shown in Tables 6 and 7.The tablet cores were coated with a coating layer comprising CA and PEGas indicated in Table 8. The drug layer compositions and swellable layercompositions are shown in Tables 9 and 10.

TABLE 6 Drug Layers (DL) 1-8 PEO Mg Mg APR: 200 Stearate Stearate DLHPMCAS kDa (IG) (EG) DL-1 50:50 − − + DL-2 50:50 + − − DL-3 50:50 − + −DL-4 50:50 + + + DL-5 50:50  0  0  0 DL-6 50:50  0  0  0 DL-7 48:52  0 0  0 DL-8 52:48  0  0  0 + 105.0% 105.0% 105.0% −  95.0%  95.0%  95.0%0 100.0% 100.0% 100.0%

TABLE 7 Swellable Layers (SL) 1-6 PEO SL 5000 kDa NaCl Mg Stearate SL-1− − + SL-2 + − − SL-3 − + − SL-4 + + + SL-5  0  0  0 SL-6  0  0  0 +105.0% 105.0% 105.0% −  95.0%  95.0%  95.0% 0 100.0% 100.0% 100.0%Percent changes of excipient addition based on standard formulation, 75mg Tablets containing DL5-8 and SL5-6

TABLE 8 TABLE 1-14 CA:PEG Tablet DL ID SL ID Coating Ratio  1 DL-6 SL-180/20  2 DL-6 SL-2 80/20  3 DL-6 SL-3 80/20  4 DL-6 SL-4 80/20  5 DL-6SL-5 80/20  6 DL-1 SL-6 80/20  7 DL-2 SL-6 80/20  8 DL-3 SL-6 80/20  9DL-4 SL-6 80/20 10 DL-5 SL-6 80/20 11 DL-7 SL-6 80/20 12 DL-8 SL-6 80/2013 DL-6 SL-6 81/19 14 DL-6 SL-6 79/21 *For all tablet cores: DL is 491.8mg; SL is 245.9 mg; and tablet core weight is 737.7 mg

TABLE 9 Drug layer compositions Composition DL5-8 DL1 DL2 DL3 DL4 % of %of % of % of % of Ingredient blend mg/tab blend mg/tab blend mg/tabblend mg/tab blend mg/tab Intragranular APR:HPMCAS 30.50 150.0 30.50150.0 30.50 150.0 30.50 150.0 30.50 150.0 PEO 200 kDa 64.0 314.75 60.80299.01 67.20 330.49 60.80 299.01 67.20 330.49 Mannitol 2.50 12.3 4.2821.04 0.74 3.62 4.28 21.04 0.71 3.48 (spray-dried) Mg stearate 0.25 1.230.24 1.17 0.24 1.17 0.26 1.29 0.26 1.29 Extragranular cSiO₂ (fumed) 0.502.46 0.50 2.46 0.50 2.46 0.50 2.46 0.50 2.46 Mannitol 2.0 9.84 3.4216.83 0.59 2.90 3.42 16.83 0.57 2.79 (spray-dried) Mg stearate 0.25 1.230.26 1.29 0.24 1.17 0.24 1.17 0.26 1.29 Total 100.0 491.8 100.0 491.8100.0 491.8 100.0 491.8 100.0 491.8

TABLE 10 Swellable layer compositions Composition SL5-6 SL1 SL2 SL3 SL4% of % of % of % of % of Ingredient blend mg/tab blend mg/tab blendmg/tab blend mg/tab blend mg/tab PEO 5000 kDa 64.90 159.59 61.66 151.6168.15 167.57 61.66 151.61 68.15 167.57 MCC 25.80 63.44 29.45 72.42 23.0156.58 28.64 70.43 22.10 54.34 NaCl 8.60 21.15 8.17 20.09 8.17 20.09 9.0322.21 9.03 22.21 Iron oxide Red 0.20 0.49 0.20 0.49 0.20 0.49 0.20 0.490.20 0.49 Mg stearate 0.50 1.23 0.53 1.29 0.48 1.17 0.48 1.17 0.53 1.29Total 100.0 245.9 100.0 245.9 100.0 245.9 100.0 245.9 100.0 245.9

Process

Drug layer blends were prepared using the procedure described herein,including blending, milling, and dry granulation using rollercompaction. A pre-granulated blend density of 0.48 g/mL was assumed tocalculate fill volumes. Blender speeds were determined by keeping theFroude number constant at approximately 0.05 across all scales.

For the drug layer pre blend, the following components were added to theblender: polyethylene oxide (e.g., PolyOx WSR-N80, MW of 200 kDa), SDD,and mannitol and blended. The pre-blend was then passed through theconical mill at slow speed, followed by blending. The lubricant (e.g.,magnesium stearate) was screened (20-mesh), added to the blender, andblended. This blended mixture was then granulated using a rollercompactor (see Table 11 for parameters). The resulting granulation wasdischarged into a container. Extragranular excipients (e.g., colloidalsilicon dioxide and mannitol) were added to the blender and mixed. Theextragranular excipient blend was then passed through the conical millat a slow speed. The granulation and this screened extragranular blendwere then combined in the blender and mixed. Lubricant (e.g., magnesiumstearate was screened (20-mesh) and added to the blender with mixing.The drug layer was discharged after blending.

The swellable layer was prepared using a similar procedure assuming abulk density of 0.41 g/mL to calculate fill volumes. The osmotic agent(e.g., sodium chloride) and colorant (e.g., iron oxide) were combined,blended using a low speed. The sodium chloride and iron oxide mixturewas then passed through a conical mill at a slow speed. The swellablepolymer (e.g., polyethylene oxide) and diluent (e.g., microcrystallinecellulose) were added to the screened mixture and blended. The combined,blended mixture is milled and blended again. Lubricant (e.g., magnesiumstearate) is screened (20-mesh), added to the blender, and blended. Theblended swellable layer mixture is discharged.

Roller compaction was conducted using the process parameters outlined inTable 11 with a target solid fraction of 0.65 in the range of 0.60-0.70.

TABLE 11 Roller compaction parameters Parameters Settings Roll SettingsMaster roll (lower, left position) Knurled Second roll (upper, rightposition) Knurled Compression force 2.0 kN/cm Press roller start speed0.5 rpm Press roller speed 4 (± 1) rpm Gap width 2 (± 0.5) mm PID3:8000:0 (unitless:msec:msec) Feed Factor 0.7 Density Ratio 0.7 FeedSettings Agitator Speed (rpm) 5 Tamp/feed ratio 300% Gap-controlactivated (on/off) On Torgue control (on/off) Off Granulator SettingsGranulator type Star rotor Granulator screen type Sguare wire meshGranulator screen size 1.0 mm Granulator rotor gap 1.0 mm (0.7-1.1 mm)Granulator speed 60 rpm Granulator CW/CCW degrees 360/400

Ribbon solid fractions for each drug layer blend were within the rangeof 0.62-0.65. Granule particle size was measured using sieve analysisfor each drug layer blend. Granulation of all drug layers using the sameprocessing parameters (Roll Speed=4.0 RPM, Roll Force=2.0 kN/cm, RollGap=2.0 mm, Mill Screen Size=1.0 mm) resulted in similar granuleparticle size distributions. The average particle size generally wasbetween 75-850 μm with populations of particles having particle sizesbetween, for example, 75-106 μm (less than 5% mass fraction), 106-150 μm(about 10% mass fraction), 150-250 μm (about 15% mass fraction), 250-500μm (about 30% mass fraction), and 500-850 μm (about 37% mass fraction).

Bilayer Tablet Compression

The final blends were compressed into fourteen tablet batches using aKorsch XM12 tablet press with process parameters summarized in Table 12.Four 12.0 mm SRC tooling stations were used to achieve a run time ofbetween 10-20 min for each formulation. All 14 tablet batches were madesuccessfully with average tablet weight, thickness, and hardness thatranged from 733.8-739.9 mg, 7.10-7.16 mm, and 14.0-16.3 kP,respectively. Average tablet weight, thickness, and hardness were withintheir acceptable ranges.

TABLE 12 Tablet Compression Parameters for Bilayer Tablets on KorschXM12 Parameter Value Tableting mode (single/bilayer) Bilayer modeTooling sizes 12.00 mm SRC (.4724″) DIA. STD CUP Tooling drawing number91558 Number of tooling stations 4 Turret speed 30 rpm Drug layer weight491.8 mg Swellable layer weight 245.9 mg Tablet core weight 737.7 mgFill Cam [10 mm] or as needed First layer feed frame paddle typeStandard sguare paddle First layer feed frame paddle speed 65 rpm(adjust speed as needed; CW rotation) Drug layer dosing depth 8.00 mmDrug layer insertion depth 3.00 mm Drug layer edge thickness 4.83 mmSecond layer feed frame paddle type 45°single bevel paddle (Korsch partnumber 80700345) Second layer feed frame paddle speed 55 rpm (adjustspeed as needed; CW rotation) Sweller layer dosing depth 6.00 mm Precompression edge thickness 4.83 mm (no pre-compression force) Maincompression edge thickness 4.23 mm Tablet hardness 15 kP Drug layertamping forced [1000 N] (Adjust as needed- avg. tamp force not to exceed1.3 kN) Pre-compression force 380 N Compression force 8.0 kN Approximatetablet thickness 7.2 mm (7.0 to 7.2 mm) De-duster Yes

Coating Layer

Tablet Cores 1-14 were coated with one of Coating Compositions A-C shownin Table 13. The coating conditions are summarized in Table 14.

Tablet Cores 1-12 were coated with Coating Composition A, Tablet Core 13was coated with Coating Composition B, and Tablet Core 14 was coatedwith Coating Composition C. The target coating wet weight gain was 7.5%.

TABLE 13 Coating Compositions A-C Ingredient Coating Coating Coating (%w/w) Comp. A Comp. B Comp. C CA  4.00  4.05  3.95 PEG 3350  1.00  0.95 1.05 Acetone 91 91 91 Purified water  4  4  4

TABLE 14 Coating Parameters for CA/PEG Coating of APR SCT Tablet Cores1-14 Process Process Parameters Target Tablet Airflow rate 40 CFMPre-heating T_(in) 45° C. T_(out) 35° C. Pan speed 3 rpm jog (jog 5 secon, 30 sec off) CA/PEG Air-flow rate 40 CFM Coating T_(out) 35° C.Atomization air pressure 10 psi Pattern air pressure 5 psiSpray-solution feed 20 g/min rate per nozzle Pan speed 22 rpm (1.3 Lpan) Gun-to-Bed Distance C 2.5 in PLC Temperature control Inlet Wetcoating weight gain 7.5 wt % Jog Drying Air-flow rate 40 CFM T_(out) 35°C. T_(in) 45° C. Pan speed 3 rpm jog (jog 5 sec on, 30 sec off)

The coated tablets were drilled using the phase 1 laser drill with a 1.2mm hole to provide the drug release orifice and subsequently pan driedfor approximately 15 hours.

Dissolution Studies

Dissolution (n=6) was performed on the Tablets 6-10 each having adifferent drug layer (DL 1-5) and the same swellable layer (SL-6). Thevariation in composition and dissolution metrics for these formulationsis presented in Table 15. The dissolution profiles for theseformulations are shown in FIG. 1 . No significant differences indissolution were observed for the five formulations. The tabletsprovided suitable dissolution profiles.

TABLE 15 Dissolution of Tablets 6-10 Mg Mg Dose PEO Stearate Stearatet₅₀ Delivered Residual t_(lag) Tablet¹ DL 200 kDa (IG) (EG) RR² (h) at 8h (%) (%) (h) 6 DL-1 − − + 5.3 8.2 49.3 23.2 1.0 7 DL-2 + − − 6.0 9.541.1 22.8 1.2 8 DL-3 − + − 5.7 9.0 44.7 25.0 1.2 9 DL-4 + + + 5.7 7.950.8 22.3 1.0 10 DL-5 0 0 0 6.1 8.2 48.6 23.7 1.2 + 105% 105% 105% − 95%  95%  95% 0 0 0 0 ¹all tablets prepared with swellable layer SL-6²zero-order release rate (RR) (5-10 h)

Dissolution (n=6) was performed on the Tablets 1-5 each having adifferent swellable layer (SL 1-5) and the same drug layer (DL-6). Thevariation in excipient amounts and key dissolution metrics is presentedin Table 16. The dissolution profiles are shown in FIG. 2 . Nosignificant difference in dissolution profile was observed for the fiveformulations. The tablets provided suitable dissolution profiles.

TABLE 16 Dissolution of Tablets 1-5 Mg Mg Dose PEO Stearate Stearate t₅₀Delivered Residual t_(lag) Tablet¹ SL 5000 kDa (IG) (EG) RR² (h) at 8 h(%) (%) (h) 1 SL-1 − − + 6.2 9.5 40.9 20.4 1.4 2 SL-2 + − − 6.5 9.3 41.922.0 1.3 3 SL-3 − + − 6.3 8.5 46.7 22.9 1.3 4 SL-4 + + + 6.3 8.5 47.421.9 1.2 5 SL-5 0 0 0 6.3 8.8 45.1 23.3 1.3 + 105% 105% 105% −  95%  95% 95% 0 0 0 0 ¹all tablets prepared with drug layer DL-6 ²zero-orderrelease rate (RR) (5-10 h)

Tablet 5 was coated with three different coating solution compositionsby varying the ratio of cellulose acetate and polyethylene glycol (PEG3350) to provide Tablets 5, 5A, and 5B. The specific ratios tested aswell as key dissolution metrics can be found in Table 17. Thedissolution profiles are shown in FIG. 3 . There was no observeddifference in the dissolution profile for the three formulations.

TABLE 17 CA/PEG coatings of Tablet 5 Dose CA:PEG t₅₀ Delivered Residualt_(lag) Tablet DL SL ratio RR¹ (h) at 8 h (%) (%) (h) 5A DL-6 SL-5 81:195.5 7.7 52.2 21.2 1.0 5   DL-6 SL-5 80:20 6.3 8.8 45.1 23.3 1.3 5B DL-6SL-5 79:21 5.6 7.8 51.4 21.2 1.1 ¹zero-order release rate (RR) (5-10 h)

Tablets 10-12 were made with SDD that had varying levels of apremilastto HPMCAS-L as outlined in Table 18, which also includes the keydissolution metrics from the study. The dissolution profiles arepresented in FIG. 4 . A slower release profile with a slight increase inresiduals was observed for the formulation containing SDD with anincreased amount of apremilast (52%) relative to the centerline SDD (50%apremilast). For this analysis, the dose per tablet for theseformulations was not normalized to the actual amounts found in theirrespective SDD lots, and centerline dose was assumed.

TABLE 18 Dissolution Results for Tablets 10-12 Dose APR:HPMCAS-L t₅₀Delivered Residual t_(lag) Tablet DL SL Ratio in SDD RR¹ (h) at 8 h (%)(%) (h) 10 DL-5 SL-6 50:50 6.1 8.2 48.6 23.7 1.2 11 DL-7 SL-6 48:52 5.48.8 46.1 23.6 1.0 12 DL-8 SL-6 52:48 4.9 10.8 39.9 26.2 1.3 ¹zero-orderrelease rate (RR) (5-10 h)

Example 3

This example demonstrates oral dosage forms in accordance withembodiments of the disclosure.

Eight tablets (Tablets 15-22) were prepared as described hereincontaining the components set forth in Table 19. The drug layers of eachof the tablets comprised apremilast and HPMCAS in weight ratio of 50:50.Further, the drug layer of Tablet 15 further comprised extragranularmannitol as a diluent. In addition, Dosage Forms 21 and 22 furthercomprised a sub-coat layer comprising hydroxypropyl methylcellulose.

TABLE 19 Tablets 15-22 Tablet 15 16 17 18 19 20 21 22 Component(mg/tablet) DRUG LAYER Intragranular Apremilast (mg) 75.0 60.0 60.0 65.065.0 70.0 75.0 75.0 HPMCAS (mg) 75.0 60.0 60.0 65.0 65.0 70.0 75.0 75.0PEO 200 kDa (mg) 314.8 307.2 307.2 332.8 332.8 358.4 314.8 314.8Mannitol (mg) 12.3 48.0 48.0 52.0 52.0 56.0 22.1 22.1 Mg stearate (mg)1.2 1.2 1.2 1.3 1.3 1.4 1.2 1.2 Extragranular cSiO₂ (mg) 2.5 2.4 2.4 2.62.6 2.8 2.5 2.5 Mannitol (mg) 9.8 — — — — — — — Mg stearate (mg) 1.2 1.21.2 1.3 1.3 1.4 1.2 1.2 SWELLABLE LAYER PEO 5000 kDa (mg) 159.6 155.8155.8 168.7 168.7 181.7 159.6 159.6 MCC (mg) 63.4 61.9 61.9 67.1 67.172.3 63.4 63.4 NaCl (mg) 21.1 20.6 20.6 22.4 22.4 24.1 21.1 21.1 Ironoxide red (mg) 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5 Mg stearate (mg) 1.2 1.21.2 1.3 1.3 1.4 1.2 1.2 Core Tablet 737.7 720.0 720.0 780.0 780.0 840.0737.7 737.7 Total wt. (mg) COATING LAYER HPMC (mg) — — — — — — 18.4 18.4Purified water* — — — — — — — — Film-coated tablet — — — — — — 756.1756.1 Total wt. (mg) CA (mg) 41.3 37.4 72.0 37.4 74.9 40.3 36.3 49.6 PEG(mg) 10.3 9.4 18.0 9.4 18.7 10.1 9.1 12.4 Acetone* — — — — — — — —Purified water* — — — — — — — — CA coated tablet 789.2 766.8 810 826.8873.6 890.4 756.1 756.1 Total wt. (mg) Opadry pink (mg) 27.6 — — — — — —— Purified water* — — — — — — — — Tablet Total wt. (mg) 816.8 766.8 810826.8 873.6 890.4 801.5 818.1 *removed during processing

Subjects were administered one of Tablets 16-22 in fed state (e.g., 30minutes after consuming a moderate- or high-fat meal).

TABLE 20 Tablets 6-22 Drug Loading Coating level Relative RelativeTablet (SDD¹) % (CA:PEG) % AUC∞ (%)¹ C_(max) (%)² Single day dosing(fasted) 16 16.7  6.5  77.4  93.2 17 16.7 12.5  66.1  68.7 18 16.7  6.0 90.1  91.4 19 16.7 12.0  58.8  64.3 20 16.7  6.0  73.1  99.3 21 20.3 6.1  66.6  91.7 22 20.3  8.4  80.2  91.6 Single day dosing (standardmeal) 21 20.3  6.1  94³ 108.9 Multiple Doses for 14 days (moderate-fatmeal) 20 16.7  6.0  80.2³  89.8 21 20.3  6.1  88.8³  93.4 22 20.3  8.4125.3³ 127.4 ¹SDD: APR:HPMCAS 1:1 ²Ratio(%) of adjusted geometric means(test/IR BID) ³AUC₀₋₂₄

Example 4

This example demonstrates oral dosage forms in accordance withembodiments of the disclosure.

Two 75 mg SCT QD apremilast tablets of Formulation 15 were prepared(Tablets A and B). Subjects were administered Tablet A (Treatment A) andTablet B (Treatment B) during the study. Treatments were administeredwith approximately 240 mL (or 8 oz) of non-carbonated, room-temperaturewater. Subjects underwent an overnight fast of at least 10 hours priorto each dosing period and for at least 4 hours after the morning dose.No food or beverages (excluding water) were allowed for at least 4 hourspostdose. Water was allowed as desired except for 1 hour prior to dosingand 1 hour postdose.

Blood samples were collected at specified time points forpharmacokinetic (PK) and clinical laboratory assessments. Safety wasmonitored throughout the study. Mean (±SD) apremilast plasmaconcentrations versus time profiles is presented in FIG. 5 . Allpharmacokinetic estimates were calculated using actual recorded blooddrawing time. Plasma pharmacokinetic parameters by treatment aresummarized in Table 21.

TABLE 21 Geometric Mean (Geometric CV %) Estimates of Apremilast PKParameters Parameter Treatment A Treatment B AUC_(0-t) (h*ng/mL) 6040(53.5) 5650 (55.2) AUC_(0-∞) (h*ng/mL) 6080 (53.5) 5680 (55.2) C_(max)(ng/mL)  382 (28.1)  357 (28.2) t_(1/2) (h)   7.2 (29.7)   7.0 (25.6)Tmax (h)^(a)   6.0(3.0-14.0)   8.0(3.0-14.0) t_(lag) (h)^(a)   0.50(0.00, 1.00)   0.50 (0.50, 1.00) CL/F (L/h)  12.3(53.5)  13.2 (55.2)V_(z)/F (L)  128 (49.8)  134 (47.4)

Following a single oral dose administration of apremilast 75 mg SCTformulation (Treatment A or Treatment B), apremilast was slowly absorbedwith maximum plasma concentrations occurring at a median time to maximumplasma concentration (T_(max)) approximately at 6 and 8 hoursrespectively. The exposures of Treatment B are slightly lower butconsidered comparable to those observed in Treatment A (C_(max): 357ng/mL vs. 382 ng/mL, AUC_(0-t):5650 h*ng/mL vs. 6040 h*ng/mL, andAUC_(0-∞): 5680 h*ng/mL vs. 6080 h*ng/mL). After achieving C_(max), theapremilast concentrations declined with terminal elimination half-life(t_(1/2)) of approximately 7 hours for both Treatment A and Treatment B.

Example 5

This example demonstrates oral dosage forms in accordance withembodiments of the disclosure.

Subjects were administered Tablet 21 once-daily during the study andcompared with a 30 mg IR apremilast formulation and a 75 mggastroretentive (GR) formulation. Treatments were administered withapproximately 240 mL (or 8 oz) non-carbonated, room-temperature water.On dosing days, subjects were fasted for at least 8 hours prior to eachmorning meal and for at least 4 hours after the morning dose. Duringfasting periods, water was allowed ad libitum except from between 1 hourprior to dosing and 1 hour postdose (excluding any water given with IP).A standard meal was administered 30 minutes prior to administration ofthe morning dose. The standard meal consisted of approximately 450calories, 25% of the calories from fat. The standard meal content wasequivalent to 8 oz of 1% fat milk, one large hard-boiled egg, two slicesof whole grain toast, one pat of butter (5 g), and one medium banana.The content (with regard to calories, fat, protein, and carbohydrates)and timing of lunch, dinner, and all snacks was consistent across allperiods on all dosing days. Lunch, dinner, and a snack were providedapproximately 4, 9, and 13 hours after the morning dose, respectively.

Blood samples were collected at specified time points forpharmacokinetic (PK) and clinical laboratory assessments. Safety wasmonitored throughout the study. Mean (±SD) apremilast plasmaconcentrations versus time profiles for both Day 1 and Day 5 arepresented in FIGS. 6 and 7 , respectively. All pharmacokinetic estimateswere calculated using actual recorded blood drawing time. Plasmapharmacokinetic parameters for all subjects who completed the treatmentsare presented are summarized in Table 22.

TABLE 22 Geometric Mean (Geometric CV %) Estimates of ApremilastPlarmacokinetic Parameters 30 mg 75 mg Day Parameter IR BID Tablet 21 GRTablet Day 1 AUC₀₋₂₄ 4090 4190 3620 (ng•h/mL) (26.9) (30.2) (27.4)AUC_(0-t) 4080 4180 3610 (ng•h/mL) (26.9) (30.1) (27.4) C_(max) (ng/mL) 351  358  406 (28.4) (27.6) (31.2) T_(max) (h)^(a)   3.00   6.00   6.00(2.00, 5.00) (4.00, 11.80) (4.00, 11.80) t_(lag) (h)   0.5   0.89   0.58(0.0) (46.8) (28.3) Day 5 AUC₀₋₂₄ 5040 5110 4010 (ng•h/mL) (29.9) (34.1)(33.1) AUC_(0-t) 6150 5980 5270 (ng•h/mL) (31.7) (38.1) (40.5) AUC_(0-∞)6210 6020 5410 (ng•h/mL) (31.2) (38.2) (42.8) C_(max) (ng/mL)  436  398 448 (24.9) (30.9) (36.4) T_(max) (h)^(a)   2.00   6.00   6.00 (1.00,5.00) (3.02, 8.00) (3.00, 24.00) t_(lag) (h)^(b) NA NA NA t_(1/2) (h)  8.11   7.13  10.4 (28.6) (32.0) (48.8) CL/F (L/h)  11.0  14.7  18.7(26.8) (34.1) (33.1) V_(z)/F (L)  129  151  280 (38.6) (30.9) (47.4)F_(rel1) (%) NA  96.9  87.2 (17.2) (36.1) F_(rel2) (%) NA  77.5  69.8(17.2) (36.1) RA   1.23   1.22   1.11 (11.0) (21.0) (36.7)

Apremilast was slowly absorbed with maximum plasma concentrationsoccurring at a median time to maximum plasma concentration (T_(max)) ofapproximately 6 hours when Tablet 21 was orally administered as a singledose and multiple doses once daily (FIG. 6 , FIG. 7 , and Table 22). Thepeak plasma concentrations of apremilast (C_(max)) were similar on Day 1between Tablet 21 and 30 mg IR BID, but C_(max) was slightly lower forTable 21 on Day 5. Table 21 exhibited a delayed median time to reachC_(max) compared to 30 mg IR BID (2 hours postdose) and a relativelylower C_(max) based on the 75 mg daily dose, reflecting a sustainedrelease effect of a typical modified release formulation (FIG. 6 , FIG.7 , and Table 22).

After achieving steady-state C_(max) on Day 5, apremilast concentrationdeclined with terminal elimination half-life (t_(1/2)) of approximately7 hours following administration of Tablet 21. The t_(1/2) of apremilastwas similar between Tablet 21 and 30 mg IR BID in healthy male subjectsfollowing multiple doses. AUC₀₋₂₄, AUC_(0-t), and AUC_(0-∞), weresimilar between Tablet 21 and 30 mg IR BID following single and multipleoral administration. The accumulation ratio of Table 21 was also similarto that of 30 mg IR BID following multiple oral doses. C_(trough) on Day5 following oral administration of Tablet 21 was lower relative to thatfor 30 mg IR BID. Relative bioavailability was comparable between Tablet21 and 30 mg IR BID, but the dose-normalized relative bioavailability ofTablet 21 was approximately 23% lower than that of 30 mg IR BID.

Apremilast was slowly absorbed with maximum plasma concentrationsoccurring at a median time to maximum plasma concentration (T_(max)) ofapproximately 6 hours when 75 mg GR Tablet was orally administered as asingle dose and multiple doses (FIG. 6 , FIG. 7 , and Table 22). Thepeak plasma concentrations of apremilast (C_(max)) for 75 mg GR Tabletwere higher than the C_(max) for IR. 75 mg GR Tablet exhibited a delayedmedian time to reach C_(max) compared to IR (2 h postdose) and arelatively lower C_(max) based on the 75 mg daily dose, reflecting asustained release effect of a typical modified release formulation (FIG.6 , FIG. 7 , and Table 22).

After achieving steady-state C_(max) on Day 5, apremilast concentrationdeclined with terminal elimination half-life (t_(1/2)) of approximately10 hours following administration of 75 mg GR Tablet. The t_(1/2) ofapremilast was 2 to 3 hours longer for 75 mg GR Tablet compared to 30 mgIR BID in healthy male subjects following multiple doses. AUC₀₋₂₄,AUC_(0-t), and AUC_(0-∞) were generally lower for 75 mg GR Tabletcompared to 30 mg IR BID following single and multiple oraladministration. The accumulation ratio and Day 5 C_(trough) for dosing75 mg GR Tablet were less compared to 30 mg IR BID following multipleoral doses (Table 22). Both relative bioavailability and thedose-normalized relative bioavailability of 75 mg GR Tablet were lowerthan those for 30 mg IR BID.

The results of the statistical analyses for AUC₀₋₂₄, C_(max), andC_(trough) for both the bioavailability of Tablet 21 apremilast QDformulation (test) and 75 mg GR Tablet apremilast QD formulation (test),relative to the 30 mg IR BID apremilast formulation (reference) aresummarized in Table 23. Day 1 and Day 5 median difference analyses ofT_(max) are summarized in Table 24.

TABLE 23 Comparison of Apremilast PK Parameters Relating Exposure AfterTablet 21 & GR Tablet 90% CI of Intra- Ratio (%) of Ratio of subjectGeometric Geometric Geometric Variability Parameter Treatment MeanComparison Means Means (%) CV % AUC₀₋₂₄ Tablet 21 5068.4 21 vs IR 100.8(90.2, 112.6) 19.8 (ng · h/mL) GR 3953.5 GR vs IR 78.6 (70.3, 87.9)  IR5029.0 C_(max) Tablet 21 399.4 21 vs IR 91.4 (78.2, 106.8) 28.1 (ng/mL)GR 448.9 GR vs IR 102.7 (87.9, 120.1) IR 437.0 C_(trough) Tablet 21 81.021 vs IR 64.1 (52.1, 78.9)  38.0 (ng/mL) GR 75.8 GR vs IR 60.0 (48.7,74.0)  IR 126.3

TABLE 24 Comparison of T_(max) of Tablet 21 & GR Tablet 90% CI of MedianMedian Day Parameter Treatment Median Comparison Difference Differencep-value 1 T_(max) (h) Tablet 21 6.02 B vs A 3.50 (2.01, 4.50) <0.0001 GR6.00 C vs A 2.50 (2.00, 3.50) <0.0001 IR 3.00 5 T_(max) (h) Tablet 216.00 B vs A 3.00 (2.50, 4.00) <0.0001 GR 5.00 C vs A 2.50 (2.00, 3.50)<0.0001 IR 2.50

Following 5-day multiple oral doses of Tablet 21 and GR Tablet oncedaily, Day 5 AUC₀₋₂₄ values were approximately 100% and 79% of thereference AUC₀₋₂₄ value, respectively. Day 5 C_(max) for Tablet 21, andGR Tablet were 91% and 103% of the reference formulation IR 30 mg BID,respectively (Table 23).

The AUC₀₋₂₄ is considered to be equivalent between the Tablet 21apremilast QD formulation and the 30 mg IR apremilast BID formulationsince the 90% Cl of the ratio of AUC₀₋₂₄ geometric means shown in Table23 was within the limits of 80% to 125%, the conventional bioequivalentcriteria. The C_(max) and C_(trough) though were approximately 9% and36% lower, respectively.

The AUC₀₋₂₄ for GR Tablet was approximately 21% lower compared to 30 mgIR BID. However, the C_(max) was considered to be equivalent between the75 mg GR Tablet apremilast QD formulation and the 30 mg IR apremilastBID formulation since the 90% Cl of the ratio of C_(max) geometric meanshown in Table 23 was within the limits of 80% to 125%, the conventionalbioequivalent criteria. The C_(trough) for GR Tablet was approximately40% lower compared to that for 30 mg IR BID.

The median T_(max) analyses are shown in Table 24. Both median values ofT_(max) of the Tablet 21 apremilast QD formulation and the 75 mg GRTablet apremilast QD formulation were significantly delayed with mediandifference from 2.5 hours to 3 hours when compared to 30 mg IRapremilast BID formulation. The median difference in T_(max) for bothtest formulations compared to reference formulation were statisticallysignificant (p<0.0001).

Example 6

This example demonstrates tablet formulations and oral dosage forms ofembodiments of the disclosure. Tablet formulations 6-1 to 6-13 wereprepared comprising the components set forth in Table 25.

TABLE 25 Core Tablet Formulations and Oral Dosage Forms of theDisclosure. Tablet 6-1 6-2 6-3 6-4 6-5 6-6 6-7 6-8 6-9 6-10 6-11 6-126-13 Component (mg/tablet) DRUG LAYER Intragranular Apremilast 100 10075 75 75 75 55 55 27.5 27.5 75 55 27.5 HPMCAS) 100 100 75 75 75 75 55 5527.5 27.5 75 55 27.5 PEO (300 kDa) 150.7 274.6 113 206 274.6 274.6 82.9151.1 41.4 75.5 — — — PEO (200 kDa) 150.7 — 113 — — — 82.9 — 41.4 —314.8 230.9 115.6 NaCl 26.7 53.3 20 40 40 40 14.7 29.3 7.3 14.7 — — —Mannitol — — — — — 25 — — — — 12.3 9 4.5 Mg stearate 1.3 1.3 1 1 1 1 0.70.7 0.4 0.4 1.2 0.9 0.5 Extragranular cSiO₂ 2.7 2.7 2 2 2 2 1.5 1.5 0.70.7 2.5 1.8 0.9 Mannitol — — — — 50 25 — — — — 9.8 7.2 3.6 Mg stearate1.3 1.3 1 1 1 1 0.7 0.7 0.4 0.4 1.2 0.8 0.5 SWELLABLE LAYER PEO (5000kDa) 173.1 173.1 129.8 129.8 173.1 173.1 95.2 95.2 47.6 47.6 159.6 11758.6 MCC 68.8 68.8 51.6 51.6 68.8 68.8 37.8 37.8 18.9 18.9 63.4 46.523.3 NaCl 22.9 22.9 17.2 17.2 22.9 22.9 12.6 12.6 6.3 6.3 21.1 15.5 7.8Iron oxide red 0.5 0.5 0.4 0.4 0.5 0.5 0.3 0.3 0.1 0.1 0.5 0.4 0.2 Mgstearate 1.3 1.3 1 1 1.3 1.3 0.7 0.7 0.4 0.4 1.2 0.9 0.5 Core Tablet800.0 799.8 600.0 600.0 785.2 785.2 440.0 439.9 219.9 220.0 737.6 540.9271.0 COATING LAYER CA 41.6 37.8 36.0 36.0 47.1 47.1 26.4 26.4 13.2 13.241.3 30.3 15.2 PEG 10.4 9.4 9.0 9.0 11.8 11.8 6.6 6.6 3.3 3.3 10.3 7.63.8 Acetone* — — — — — — — — — — — — — Purified water* — — — — — — — — —— — — — CA coated tablet 852.0 847.0 645.0 645.0 844.1 844.1 473.0 472.9236.4 236.5 789.2 578.8 290.0 Total wt. (mg) Opadry pink — — — — — — — —— — 27.6 20.2 10.1 Purified water* — — — — — — — — — — — — — TabletTotal wt. (mg) 852.0 847.0 645.0 645.0 844.1 844.1 473.0 472.9 236.4236.5 816.8 599.0 300.1

Example 7

This example demonstrates 100 mg core tablet formulations of embodimentsof the disclosure. 100 mg core tablet formulations 7-1 through 7-6 wereprepared comprising the drug layer components set forth in Table 26.Each of 7-1 through 7-6 comprised the same swellable layer comprisingthe following components (wt % of swellable layer): 64.9% PEO, 25.8%MCC, 8.6% NaCl, 0.2% iron oxide red; and 0.5% Mg stearate. Each druglayer in 7-1 through 7-6 had a total weight of 533.3 mg and theswellable layer had a weight 266.7 mg providing for a total, uncoatedweight of 800 mg for each tablet core composition.

TABLE 26 Core Tablet Compositions 7-1 through 7-6 (100 mg) Core TabletComp. 7-1 7-2 7-3 7-4 7-5 7-6 Component Drug Layer Intragranular (%blend) 50% APM:HPMCAS-L SDD 37.5 37.5 37.5  37.5 37.5 37.5 PEO (200 kDa)61.50 30.75 — 51.50 25.75 — PEO (600 kDa) — 30.75 61.50  — 25.75 51.50NaCl — — — 10.0 10.0 10.0 Mg stearate 0.25 0.25 0.25 0.25 0.25 0.25Extragranular (% blend) cSiO₂ 0.50 0.50 0.50 0.50 0.50 0.50 Mg stearate0.25 0.25 0.25 0.25 0.25 0.25

The dissolution of core tablet formulations 7-1 through 7-6 was analyzedunder the following conditions: Apparatus used: USP Apparatus 2(Paddles); Vessel: 1 L dissolution vessel with low evaporation lids;Paddle stirring speed: 75±2 rpm; Dissolution medium temperature:37.0±0.5° C.; Sample size: one tablet per vessel; Dissolution mediumcomposition: 0.5% Tween®80 in sodium acetate buffer, pH 5.5; Dissolutionmedium volume: 900 mL; Sample volume: 1.5 mL (auto-sampler) or 5 mL(manual sampling).

The results are shown in Table 27 and FIG. 8 .

TABLE 27 Dissolution of Core Tablet Compositions Described in Table 26Zero- order Core Tablet Lag Residual RR Composition Time (h) (%) t₇₀ (h)(%/h)¹ 7-1 1.0 38 NA 3.8 7-2 2.4 22 19.5 4.9 7-3 4.3 33 NA 4.5 7-4 0.459 NA 2.2 7-5 2.2 19  9.8 9.3 7-6 3.4 12 11.3 9.5 ¹release ratecalculated between 5-10 h

As shown in Table 27 and FIG. 8 , dissolution at 24 h increases withincreasing fraction of high molecular weight PEO in the presence of theosmotic agent in the drug layer. Further, lag time increases with MW ofPEO and is shorter in the presence of the osmotic agent in the druglayer. The residual apremilast remaining is highest for Tablet CoreComposition 7-4 and decreases for Tablet Core Compositions 7-5 and 7-6with increasing high molecular weight PEO (600 kDa) fraction and osmoticagent (e.g., NaCl). An overall improvement in dissolution performancefor formulations with high MW PWO in the presence of an osmotic agent isobserved (7-2 vs. 7-5 and 7-3 vs. 7-6).

Next, core tablet compositions 7-7 through 7-12 were prepared comprisingthe drug layers shown in Table 28 and same swellable layer as above.

TABLE 28 Core Tablet Compositions 7-7 through 7-12 (100 mg) Core TabletComp. 7-7 7-8 7-9 7-10 7-11 7-12 Component Drug Layer Intragranular (%blend) 50% APM:HPMCAS-L SDD 37.5 37.5 37.5 37.5 37.5 37.5 PEO (300 kDa)30.75 28.25 25.75 61.50 56.50 51.50 PEO (200 kDa) 30.75 28.25 25.75 — —— NaCl — 5.0 10.0 — 5.0 10.0 Mg stearate 0.25 0.25 0.25 0.25 0.25 0.25Extragranular (% blend) cSiO₂ 0.50 0.50 0.50 0.50 0.50 0.50 Mg stearate0.25 0.25 0.25 0.25 0.25 0.25

The dissolution of compositions 7-7 through 7-12 were evaluated usingthe same conditions as above.

The results are shown in Table 29 and FIG. 9 .

TABLE 29 Dissolution of Core Tablet Compositions Described in Table 28Zero- order Core Tablet Lag Residual RR Composition Time (h) (%) t₇₀ (h)(%/h)¹ 7-7 1.4 16 15.2 5.8 7-8 1.9 19 11.5 7.5 7-9 2 27 13.7 7.0 7-102.9 20 17.7 5.2 7-11 2.7 14 11.0 7.6 7-12 1.9 14 10.3 8.3 ¹release ratecalculated between 5-10 h

As shown in Table 29 and FIG. 9 , both lag time and % residualapremilast remaining increase with increasing osmotic agent in the druglayer for in Compositions 7-7 through 7-9, containing a mixture of thetwo PEO grades. Lag time and residual apremilast decrease or remain thesame with increasing osmotic agent for Compositions with high MW PEO(7-10 through 7-12). Composition 7-12 exhibited desirable performancewith the lowest amount of residual apremilast and a short lag time whilecomprising a single grade of PEO and 10% NaCl.

In general, the minimization of residuals during dissolution was afunction of both the concentration of sodium chloride and molecularweight of the PEO in the drug layer, with the lowest residuals found inthe formulation with 10% sodium chloride and highest MW PEO (PolyOx WSR205, MW=600 kDa). Increased amounts of sodium chloride (5% and 10% ofdrug layer) decrease the lag time and increase release rate forcompositions with high MW PEO (7-3 vs 7-6 and 7-10 to 7-12). Theshortest lag time was observed in the formulation with 10% NaCl andlowest molecular weight PEO (PolyOx WSR N80, MW=200 kDa). The desirableformulation would reduce residuals and lag time with the simplestformulation; therefore, Formulation 7-12 was the best overall performerfrom both Round 1 and Round 2 with a lag time of 1.9 h, residuals of14%, and using only one grade of PEO (PolyOx WSR N750 LEO) with 10%sodium chloride.

In stability studies, core tablet formulation 7-8 showed some degree ofcrystallinity by PXRD and decreased dissolution after 3 months and 6months at 40° C./75% relative humidity (FIGS. 10A and 10B). In contrast,core tablet composition 7-12 showed no crystallinity or changes indissolution after 6 months at 40° C./75% RH (FIGS. 11A and 11B). Coretablet composition 7-8 showed no changes at 30° C./65% RH at 3-months or6-months (FIGS. 10B and 11B). In order to ensure the sensitivity of PXRDmethod to detect crystalline drug in the formulation samples onstability, 0.5% milled API in SDD standard was used as a control inthese measurements (FIGS. 10B and 11B).

No changes in dissolution or crystallinity were observed for 7-8 and7-12 at 25° C./60% RH and 30° C./65% RH while 7-12 remained stable underthese conditions. It was determined that undissolved drug in thedissolution medium in combination with residual in the tablet accountfor the difference in % dose dissolved for samples with decreasedperformance (approximately 10-15% residual drug in tablet shell isexpected for this formulation) (FIG. 10A). Acetonitrile (ACN) was addedafter the 24 hour timepoint and bath homogenization in order to ensurecomplete dissolution of the residual drug in the tablet (FIGS. 10A and11A).

These data demonstrate that high MW PEO in the drug layer is beneficialto ensure adequate dissolution performance at accelerated stabilityconditions of 30° C./65% RH and 40° C./75% RH. The presence of NaCl inthe drug layer in these situations ensures adequate lag time.

The foregoing examples are merely illustrative of embodiments of thedisclosed processes described herein and are not intended to limit thedisclosed methods. Variations and changes which are obvious to oneskilled in the art are intended to be within the scope and nature of thedisclosure which is defined in the appended claims.

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing embodiments of thedisclosure (especially in the context of the following claims) are to beconstrued to cover both the singular and the plural, unless otherwiseindicated herein or clearly contradicted by context. The use of the term“at least one” followed by a list of one or more items (for example, “atleast one of A and B”) is to be construed to mean one item selected fromthe listed items (A or B) or any combination of two or more of thelisted items (A and B), unless otherwise indicated herein or clearlycontradicted by context. The terms “comprising,” “having,” “including,”and “containing” are to be construed as open-ended terms (i.e., meaning“including, but not limited to,”) unless otherwise noted. Recitation ofranges of values herein are merely intended to serve as a shorthandmethod of referring individually to each separate value falling withinthe range, unless otherwise indicated herein, and each separate value isincorporated into the specification as if it were individually recitedherein. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (for example, “such as”) provided herein, is intended merely tobetter illuminate embodiments of the disclosure and does not pose alimitation on the scope of the disclosure unless otherwise claimed. Nolanguage in the specification should be construed as indicating anynon-claimed element as essential to the practice of the disclosure.

1.-79. (canceled)
 80. An oral dosage form comprising: a core tabletcomprising (i) a drug layer comprising 8-11 wt % apremilast based upontotal core tablet weight, 8-11 wt % hypromellose acetate succinate(HPMCAS) based upon total core tablet weight, 2-7 wt % mannitol basedupon total core tablet weight, 40-45 wt % polyethylene oxide withmolecular weight of 200,000 Da based upon total core tablet weight,0.1-0.5 wt % magnesium stearate based upon total core tablet weight, and0.1-0.5 wt % colloidal silicon dioxide based upon total core tabletweight, wherein the apremilast and HPMCAS are in a solid dispersion; and(ii) a swellable layer comprising 18-25 wt % polyethylene oxide withmolecular weight of 5,000,000 Da based upon total core tablet weight,7-10 wt % microcrystalline cellulose based upon total core tabletweight, 1.5-3.5 wt. % sodium chloride based upon total core tabletweight, 0.01-0.2 wt % iron oxide based upon total core tablet weight,and 0.05-0.3 wt % magnesium stearate based upon total core tabletweight; and a coating layer disposed on the core tablet and comprisingcellulose acetate and polyethylene glycol; and the oral dosage formsurface comprises at least one drug release orifice.
 81. The oral dosageform of claim 80, wherein the drug layer comprises 75 mg apremilast, 75mg hypromellose acetate succinate (HPMCAS), 22.1 mg mannitol, 314.8 mgpolyethylene oxide with molecular weight of 200,000 Da, 2.4 mg magnesiumstearate, and 2.5 mg colloidal silicon dioxide; and the swellable layercomprises 159.6 mg polyethylene oxide with molecular weight of 5,000,000Da, 63.4 mg microcrystalline cellulose, 21.1 mg sodium chloride, 0.5 mgiron oxide, and 1.2 mg magnesium stearate.
 82. The oral dosage form ofclaim 80, wherein the drug layer comprises 55 mg apremilast, 55 mghypromellose acetate succinate (HPMCAS), 16.2 mg mannitol, 230.9 mgpolyethylene oxide with molecular weight of 200,000 Da, 1.7 mg magnesiumstearate, and 1.8 mg colloidal silicon dioxide; and the swellable layercomprises 117 mg polyethylene oxide with molecular weight of 5,000,000Da, 46.5 mg microcrystalline cellulose, 15.5 mg sodium chloride, 0.4 mgiron oxide, and 0.9 mg magnesium stearate.
 83. The oral dosage form ofclaim 80, wherein the drug layer comprises 27.5 mg apremilast, 27.5 mghypromellose acetate succinate (HPMCAS), 8.1 mg mannitol, 115.6 mgpolyethylene oxide with molecular weight of 200,000 Da, 1.0 mg magnesiumstearate, and 0.9 mg colloidal silicon dioxide; and the swellable layercomprises 58.6 mg polyethylene oxide with molecular weight of 5,000,000Da, 23.3 mg microcrystalline cellulose, 7.8 mg sodium chloride, 0.2 mgiron oxide, and 0.5 mg magnesium stearate.
 84. An oral dosage formcomprising: a core tablet comprising (i) a drug layer comprising 9-15wt. % apremilast based upon total core tablet weight, 10-15 wt %hypromellose acetate succinate (HPMCAS) based upon total core tabletweight, 0-27 wt % mannitol based upon total core tablet weight, 30-40 wt% polyethylene oxide with molecular weight of 200,000 to 300,000 Da or amixture thereof based upon total core tablet weight, 2-8 wt % sodiumchloride based upon total core tablet weight, 0.1-0.5 wt % magnesiumstearate based upon total core tablet weight, and 0.1-0.5 wt % colloidalsilicon dioxide based upon total core tablet weight, wherein theapremilast and HPMCAS are in a solid dispersion; and (ii) a swellablelayer comprising 15-25 wt % polyethylene oxide with molecular weight of5,000,000 Da based upon total core tablet weight, 5-10.0 wt %microcrystalline cellulose based upon total core tablet weight, 2-4 wt %sodium chloride based upon total core tablet weight, 0.01-0.1 wt % ironoxide based upon total core tablet weight, and 0.05-0.3 wt % magnesiumstearate based upon total core tablet weight; and a coating layerdisposed on the core tablet and comprising cellulose acetate andpolyethylene glycol; and the oral dosage form surface comprises at leastone drug release orifice.
 85. The oral dosage form of claim 84, whereinthe drug layer comprises 100 mg apremilast, 100 mg hypromellose acetatesuccinate (HPMCAS), 301.4 mg polyethylene oxide with molecular weight of200,000 to 300,000 Da or a mixture thereof, 26.7 mg sodium chloride, 2.6mg magnesium stearate, and 2.7 mg colloidal silicon dioxide; and theswellable layer comprises 173.1 mg polyethylene oxide with molecularweight of 5,000,000 Da, 68.8 mg microcrystalline cellulose, 22.9 mgsodium chloride, 0.5 mg iron oxide, and 1.3 mg magnesium stearate. 86.The oral dosage form of claim 84, wherein the drug layer comprises 100mg apremilast, 100 mg hypromellose acetate succinate (HPMCAS), 274.6 mgpolyethylene oxide with molecular weight of 300,000 Da, 53.3 sodiumchloride, 2.6 mg magnesium stearate, and 2.7 mg colloidal silicondioxide; and the swellable layer comprises 173.1 mg polyethylene oxidewith molecular weight of 5,000,000 Da, 68.8 mg microcrystallinecellulose, 22.9 mg sodium chloride, 0.5 mg iron oxide, and 1.3 mgmagnesium stearate.
 87. The oral dosage form of claim 84, wherein thedrug layer comprises 75 mg apremilast, 75 mg hypromellose acetatesuccinate (HPMCAS), 226.0 mg polyethylene oxide with molecular weight of200,000 to 300,000 Da or a mixture thereof, 20.0 mg sodium chloride, 2.0mg magnesium stearate, and 2.0 mg colloidal silicon dioxide; and theswellable layer comprises 129.8 mg polyethylene oxide with molecularweight of 5,000,000 Da, 51.6 mg microcrystalline cellulose, 17.2 mgsodium chloride, 0.4 mg iron oxide, and 1.0 mg magnesium stearate. 88.The oral dosage form of claim 84, wherein the drug layer comprises 75 mgapremilast, 75 mg hypromellose acetate succinate (HPMCAS), 206.0 mgpolyethylene oxide with molecular weight of 300,000 Da, 40.0 mg sodiumchloride, 2.0 mg magnesium stearate, and 2.0 mg colloidal silicondioxide; and the swellable layer comprising 129.8 mg polyethylene oxidewith molecular weight of 5,000,000 Da, 51.6 mg microcrystallinecellulose, 17.2 mg sodium chloride, 0.4 mg iron oxide, and 1.0 mgmagnesium stearate.
 89. The oral dosage form of claim 84, wherein thedrug layer comprises 55 mg apremilast, 55 mg hypromellose acetatesuccinate (HPMCAS), 165.7 mg polyethylene oxide with molecular weight of200,000 to 300,000 Da or a mixture thereof, 14.7 mg sodium chloride, 1.4mg magnesium stearate, and 1.5 mg colloidal silicon dioxide; and theswellable layer comprises 95.2 mg polyethylene oxide with molecularweight of 5,000,000 Da, 37.8 mg microcrystalline cellulose, 12.6 mgsodium chloride, 0.3 mg iron oxide, and 0.7 mg magnesium stearate. 90.The oral dosage form of claim 84, wherein the drug layer comprises 55 mgapremilast, 55 mg hypromellose acetate succinate (HPMCAS), 151.1 mgpolyethylene oxide with molecular weight of 300,000 Da, 29.3 mg sodiumchloride, 1.4 mg magnesium stearate, and 1.5 mg colloidal silicondioxide; and the swellable layer comprises 95.2 mg polyethylene oxidewith molecular weight of 5,000,000 Da, 37.8 mg microcrystallinecellulose, 12.6 mg sodium chloride, 0.3 mg iron oxide, and 0.7 mgmagnesium stearate.
 91. The oral dosage form of claim 84, wherein thedrug layer comprises 27.5 mg apremilast, 27.5 mg hypromellose acetatesuccinate (HPMCAS), 82.9 mg polyethylene oxide with molecular weight of200,000 to 300,000 Da or a mixture thereof, 7.3 mg sodium chloride, 0.8mg magnesium stearate, and 0.7 mg colloidal silicon dioxide; and theswellable layer comprises 47.6 mg polyethylene oxide with molecularweight of 5,000,000 Da, 18.9 mg microcrystalline cellulose, 6.3 mgsodium chloride, 0.1 mg iron oxide, and 0.4 mg magnesium stearate. 92.The oral dosage form of claim 84, wherein the drug layer comprises 27.5mg apremilast, 27.5 mg hypromellose acetate succinate (HPMCAS), 75.5 mgpolyethylene oxide with molecular weight of 300,000 Da, 14.7 mg sodiumchloride, 0.4 mg magnesium stearate, and 0.7 mg colloidal silicondioxide; and the swellable layer comprises 47.6 mg polyethylene oxidewith molecular weight of 5,000,000 Da, 18.9 mg microcrystallinecellulose, 6.3 mg sodium chloride, 0.1 mg iron oxide, and 0.4 mgmagnesium stearate.
 93. A method of treating a patient suffering from adisease or disorder ameliorated by inhibiting PDE4 comprisingadministering to the patient the oral dosage form of claim 80 once dailyunder fed conditions.
 94. The method of claim 93, wherein the disease ordisorder is psoriasis, psoriatic arthritis, or Behcet's disease.
 95. Amethod of treating a patient suffering from a disease or disorderameliorated by inhibiting PDE4 comprising administering to the patientthe oral dosage form of claim 84 once daily under fed conditions. 96.The method of claim 95, wherein the disease or disorder is psoriasis,psoriatic arthritis, or Behcet's disease.